Quinolone derivative or salt thereof and antibacterial containing the same

ABSTRACT

PCT No. PCT/JP92/01712 Sec. 371 Date Aug. 19, 1993 Sec. 102(e) Date Aug. 19, 1993 PCT Filed Dec. 25, 1992 PCT Pub. No. WO93/13091 PCT Pub. Date Aug. 7, 1993.A quinolone derivative represented by the below-described formula (1), or a salt thereof:    &lt;IMAGE&gt;  (1)  wherein R1 represents a hydrogen atom, or a carboxyl protective group, R2 represents a hydrogen atom, halogen atom or a lower alkyl group, X represents a hydrogen atom or a halogen atom, Y represents a halogen atom, a cyclic amino group which may have a substituent, a cyclo- lower alkenyl group which may have a substituent, or a group R3-(CH2)m-A- (wherein R3 represents a hydrogen atom or an amino group which may have a substituent, A represents an oxygen atom or a sulfur atom and m represents a number of 0 to 3), Z represents a nitrogen atom or a group C-R4 (wherein R4 represents a hydrogen atom or a halogen atom), W represents a five-membered heterocyclic group which may have a substituent and which has 3 or more hetero-atoms, among which at least 2 hetero-atoms are nitrogen atoms, and n represents a number of 0 to 2; and an antibacterial agent containing the compounds. Since the above-mentioned compounds exhibit excellent antibacterial activities and are highly safe, they are useful as pharmaceuticals for the human and animals, medicines for fishes, pesticides, preservatives for foods, and the like.

This application is a 371 of PCT/JP 92/01712, filed Dec. 25, 1992.

TECHNICAL FIELD

The present invention relates to novel quinolone derivatives and saltsthereof having excellent antibacterial activity and oral-routeabsorption, and antibacterial agents containing the compounds.

BACKGROUND ART

Among the compounds which have pyridonecarboxylic acid as a basicskeleton, many are known to be useful as synthetic antibacterial agentsdue to their excellent antibacterial activities and a broadantibacterial spectrum. Mention may be given to norfloxacin (JapanesePatent Application Kokai No. 141286/1978), enoxacin (Japanese PatentApplication Kokai No. 31042/1980), ofloxacin (Japanese PatentApplication Kokai No. 46986/1982), cyprofloxacin (Japanese PatentApplication Kokai No. 76667/1983) and the like, which have widely founda clinical utility as therapeutic agents for infectious diseases.

These compounds, however, are not sufficiently satisfactory in terms ofantibacterial activities, intestinal tract absorption, metabolicstability, minimized adverse side effects, and the like, and hence novelcompounds which meet these requirements have been desired.

Under the above circumstances, the present inventors have conductedcareful studies with a view toward obtaining clinically excellentsynthetic antibacterial agents, and have found that the compoundsrepresented by formula (1) described hereinafter provide excellent oralabsorption, exhibit excellent antibacterial activities against gramnegative and gram positive bacteria and thus are very useful assynthetic antibacterial agents, leading to the completion of theinvention.

DISCLOSURE OF THE INVENTION

The present invention is to provide quinolone derivatives represented bythe below-described formula (1), salts thereof and antibacterial agentscontaining the derivatives or salts: ##STR2## wherein R¹ represents ahydrogen atom, halogen atom or a carboxyl protective group, R²represents a hydrogen atom, halogen atom or a lower alkyl group, Xrepresents a hydrogen atom or a halogen atom, Y represents a halogenatom, a cyclic amino group which may have a substituent, a cyclo- loweralkenyl group which may have a substituent, or a group R³ --(CH₂)_(m)--A--(wherein R³ represents a hydrogen atom or an amino group which mayhave a substituent, A represents an oxygen atom or a sulfur atom and mrepresents a number of 0 to 3), Z represents a nitrogen atom or a groupC--R⁴ (wherein R⁴ represents a hydrogen atom or a halogen atom), Wrepresents a five-membered heterocyclic group which may have asubstituent and which has 3 or more hetero-atoms, among which at least 2hetero-atoms are nitrogen atoms, and n represents a number of 0 to 2.

Since the present compounds (1) exhibit excellent antibacterialactivities and are highly safe, they are useful as pharmaceuticals forthe human and animals, medicines for fishes, pesticides, preservativesfor foods, and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, the term "lower" used in the expressions ofthe substituents of the quinolone derivatives or their salts (1) meansthat the group referred to has 1-7, preferably 1-5 carbon atoms when thesubstituents are linear or branched, and has 3-7 carbon atoms when thesubstituents are cyclic.

The carboxy protective group represented by R¹ is the ester residue of acarboxylic acid ester, and encompasses any groups which are relativelyeasily cleaved and produce corresponding free carboxyl groups. Examplesof the carboxy protective group include those removable upon treatmentunder mild conditions such as hydrolysis or catalytic reduction, such aslower alkyl groups (e.g., methyl, ethyl, n-propyl, t-butyl, etc.), loweralkenyl groups (e.g., allyl, etc.), aralkyl groups (e.g., benzyl, etc.)or aryl groups (e.g., phenyl, etc.); and those readily removable in aliving body, such as lower alkanoyloxy-lower alkyl groups (e.g.,acetoxymethyl, pivaloyloxymethyl, etc.), lower alkoxycarbonyloxy-loweralkyl groups (e.g., methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl,etc.), lower alkoxymethyl groups (e.g. methoxymethyl, etc.), lactonylgroups (e.g., phthalidyl, etc.), di(lower alkyl)amino-lower alkyl groups(e.g., 1-dimethylaminoethyl, etc.),(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, and the like.

Examples of lower alkyl groups represented by R² include methyl group,ethyl group, n-propyl group and t-butyl group.

Examples of halogen atoms represented by X and R² include a fluorineatom, chlorine atom, bromine atom, with a fluorine atom being preferred.

Halogen atoms represented by Y are the same as those represented by X,among which a fluorine atom and a chlorine atom are preferred.

Cyclic amino groups, represented by Y, which may have a substituent aresaturated or unsaturated, and they may contain further one or morehetero-atoms such as nitrogen, oxygen, sulfur, etc., or a carbonylcarbon in the ring thereof. They may be mono, di, or tri-cyclic.Examples of such cyclic amino groups include: saturated or unsaturatedmonocyclic 3 to 7 membered cyclic amino groups having one nitrogen atom,such as azirydin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrrolin-1-yl,pyrrol-1-yl, dihydropyridin-1-yl, piperidino, dihydroazepin-1-yl,perhydroazepin-1-yl; saturated or unsaturated monocyclic 3 to 7 memberedcyclic amino groups having two nitrogen atoms, such as imidazol-1-yl,imidazolidin-1-yl, imidazolin-1-yl, pyrazolidin-1-yl, piperazin-1-yl, 1,4-dihydropyridin-1-yl, 1,2-dihydropyrimidin-1-yl, perhydropyrazin-1-yland homopiperazin-1-yl; saturated or unsaturated monocyclic 3 to 7membered cyclic amino groups having three or more nitrogen atoms, suchas 1,2,4-triazole-1-yl, 1,2,3-triazole-1-yl,1,2-dihydro-1,2,4-triazin-1-yl and perhydro-S-triazin-1-yl; saturated orunsaturated monocyclic 3 to 7 membered cyclic amino group which has ahetero-atom selected from the group consisting of nitrogen, oxygen andsulfur, as well as a nitrogen atom, such as oxazolidin-3-yl,isoxazolidin-2-yl, morpholino, 1,3-oxazin-3-yl, tiazolidin-1-yl,isotiazolidin-1-yl, thiomorpholin-1-yl, homothiomorpholin-1-yl,1,2,4-thiadiazolin-2-yl, 1,2,3-thiadiazolidin-2-yl; saturated orunsaturated monocyclic cyclic amino groups of di or tri-cyclic, such asisoindolin-2-yl, indolin-1-yl, 1H-indazol-1-yl, purin-7-yl andtetrahydroquinolin-1-yl; and spiro or bridge type, saturated orunsaturated 5 to 12 membered cyclic amino groups, such as2,8-diazaspiro[4,4]nonan-2-yl, 7-azabicyclo-[2.2.1]heptan-7-yl,2,8-diazabicyclo-[4,3,0]nonane, 5-methyl-2,5-diazabicyclo[2.2.1]heptaneand 2,5-diazabicyclo[2.2.1]heptane. Preferred examples of such cyclicamino groups are those represented by the following formulas (a)-(t):##STR3##

In the above formulas, E is an oxygen atom, a sulfur atom, --NR⁷ or--CONR⁷ (R⁷ is a hydrogen atom, a hydroxyl group, a lower alkyl group, acyclo- lower alkyl group, an aralkyl group, an alkenyl group, and acylgroup or a hydroxy- lower alkyl group), G is CH or N, e is a number of3-5, f is a number of 1-3, g is a number of 0-2 and h is 3 or 4, i is 1or 2.

Cyclic atoms of these cyclic amino groups may be substituted withsuitable substituents. Preferable examples of such substituents includelower alkyl groups, lower alkenyl groups, lower aralkyl groups, arylgroups, hydroxyl groups, hydroxy-lower alkyl groups, substituted orunsubstituted amino groups, substituted or unsubstituted amino- loweralkyl groups, cyclic amino groups as mentioned above, alkoxy groups,alkoxy- lower alkyl groups, halogen atoms, halo- lower alkyl groups,acyloxy groups, acyloxy- lower alkyl groups, acyl groups, carboxylgroups, carboxy- lower alkyl groups, alkoxycarbonyl- lower alkyl groups,mercapto groups, lower alkylthio groups, cyano groups and nitro groups.

Examples of the lower alkyl groups include methyl group and ethyl group,n-propyl group and the like. Examples of the lower alkenyl groupsinclude vinyl group and allyl group and the like. Examples of the loweraralkyl groups include benzyl group and 1-phenylethyl group and thelike. Examples of the aryl groups include phenyl group and the like.Examples of the hydroxy-lower alkyl groups include hydroxymethyl group,hydroxyethyl group, hydroxypropyl group and the like. Examples of theamino-lower alkyl groups include aminomethyl group, 1-aminoethyl group,2-aminoethyl group, 1-amino-1-methylethyl group and the like. Examplesof the alkoxy groups include methoxy group, ethyoxy group, n-propoxygroup and the like. Examples of the alkoxy-lower alkyl groups includemethoxymethyl group, ethoxymethyl group and the like. Examples of thehalogen atoms include fluorine atom, chlorine atom, bromine atom and thelike. Examples of the halo- lower alkyl groups include fluoromethylgroup, trifluoromethyl group and the like. Examples of the acyloxygroups include acetoxy group, benzoyloxy group and the like. Examples ofthe acyloxy- lower alkyl groups include acetoxymethyl groupbenzoyloxymethyl group and the like. Examples of the acyl groups includelower alkanoyl group such as formyl, acetyl and the like, loweralkoxycarbonyl group such as methoxycarbonyl and ethoxycarbonyl, andaromatic acyl group such as benzoyl, phenoxycarbonyl, and the like.Examples of the carboxy- lower alkyl groups include carboxymethyl group,carboxyethyl group and the like. Examples of the alkoxycarbonyl-loweralkyl groups include methoxycarbonylmethyl group, t-butoxycarbonylmethylgroup and the like. Examples of the lower alkylthio groups includemethylthio group, ethylthio group and the like.

As the substituent of the substituted amino group and the substitutedamino- lower alkyl group, there can be mentioned lower alkyl groups(e.g., methyl group, ethyl group, etc.), lower cycloalkyl groups (e.g.,cyclopropyl group, cyclobutyl group, cyclopentyl group, etc.), loweralkenyl groups (e.g., vinyl group, ally group, etc.), lower aralkylgroups (e.g., benzyl group, 1-phenylethyl group, etc.), aryl groups(e.g., phenyl group, etc.), acyl groups (e.g., lower alkanoyl groupssuch as formyl and acetyl, lower alkoxycarbonyl groups such asmethoxycarbonyl and ethoxycarbonyl, etc.), amino acid residues orpeptide residues (e.g., glycyl-, leucyl-, valyl, alanyl-, phenylalanyl-,alanyl-alanyl, glycyl-valyl and glycyl-glycyl-valyl- groups, etc.),amino acid residues or peptide residues such as the above-describedgroups protected by a protection group such as acyl group, lower aralkylgroup or the like commonly used in the peptide chemistry; and cyclicamino groups. The same or different kinds of 1 to 2 substituents can befreely selected. Compounds protected by the above-mentioned amino acidresidues or peptide residues expectedly have an improvedwater-solubility.

Preferable examples of the substituted amino group and the substitutedamino- lower alkyl group include methylamino group, ethylamino group,dimethylamino group, methylaminomethyl group, ethylaminomethyl group,dimethylaminomethyl group, glycyl-amino group, leucyl-amino group,valyl-amino group, alanyl-amino group, alanyl-alanyl-amino group and thelike.

Regarding the groups represented by R⁷,there are given methyl group,ethyl group or the like for the lower alkyl group; cyclopropyl group,cyclobutyl group or the like for the cyclo-lower alkyl group; benzylgroup, 1-phenylethyl group or the like for the aralkyl group; vinylgroup, allyl group or the like for the alkenyl group; formyl group,acetyl group, methoxycarbonyl group, ethoxycarbonyl group or the likefor the acyl group; and hydroxymethyl group, hydroxyethyl group or thelike for the hydroxy- lower alkyl group.

Among the cyclic amino groups represented by the formulas (a) and (b),those represented by the following formulas (a') and (b') areparticularly preferred. ##STR4## wherein E, e, f and g have the samemeaning as defined for the formulas (a) and (b), j¹, j² and j³ may bethe same or different and are one of a hydrogen atom, a lower alkylgroup, a lower alkenyl group, a lower aralkyl group, an aryl group, ahydroxyl group, a hydroxy- lower alkyl group, a amino group which mayhave a substituent, a amino- lower alkyl group which may have asubstituent, a pyrrolidinyl group, a piperidino group, an azetidinylgroup, an alkoxy group, an alkoxy- lower alkyl group, a halogen atom, ahalo- lower alkyl group, an acyloxy group, an acyloxy- lower alkylgroup, an acyl group, a carboxyl group, a carboxy- lower alkyl group, analkoxycarbonyl- lower alkyl group, a mercapto group, a lower alkylthiogroup, a cyano group and nitoro group.

The definitions of substituents of the j¹, j² and j³ and theirpreferable examples are the same as those described in relation to thesubstituents for the above-mentioned cyclic amino groups.

Examples of the heterocyclic ring groups represented by formula (a')include azetidinyl group, pyrrolidinyl group and piperidino group.Examples of the heterocyclic ring groups represented by formula (b')include piperazinyl group, morpholino group, thiomorpholino group,homopiperazinyl group, thiazolidinyl group, oxazolidinyl group and3-oxo-1-piperazinyl group.

Particularly, preferable examples of groups represented by formulas (a')and (b') are as follows:

3-hydroxyazetidinyl group, 3-aminoazetidinyl group,3-(N-t-butoxycarbonylamino)azetidinyl group, 3-acetylamino-azetidinylgroup, 3-methylaminoazetidinyl group, 3-dimethyl-aminoazetidinyl group,3-methylazetidinyl group, 3-amino-2-methylazetidinyl group; pyrrolidinylgroup, 3-hydroxy- pyrrolidinyl group, 3,4-dihydroxypyrrolidinyl group,3-methoxypyrrolidinyl group, 3-methylpyrrolidinyl group,3-hydroxy-4-methyl-pyrrolidinyl group, 3-aminopyrrolidinyl group,3-methylaminopyrrolidinyl group, 3-dimethylamino pyrrolidinyl group,3-ethylaminopyrrolidinyl group, 3-diethylaminopyrrolidinyl group,3-acetylaminopyrrolidinyl group, 3-t-butoxycarbonylaminopyrrolidinylgroup, 3-(N-acetyl)methylaminopyrrolidinyl group,3-(t-butoxy-carbonyl)methylaminopyrrolidinyl group,3-amino-methylpyrrolidinyl group, 3-methylaminomethylpyrrolidinyl group,3-dimethylaminomethylpyrrolidinyl group; 3-ethylaminomethylpyrrolidinylgroup, 3-diethylaminomethylpyrrolidinyl group,3-(N-acetyl)aminomethylpyrrolidinyl group,3-(t-butoxycarbonyl)aminomethylpyrrolidinyl group,3-(N-acetyl)methylaminomethylpyrrolidinyl group,3-(t-butoxy-carbonyl)methylaminomethylpyrrolidinyl group,3-(1-amino-ethyl)pyrrolidinyl group, 3-(2-aminoethyl)pyrrolidinyl group,3-(1-amino-1-methylethyl)pyrrolidinyl group,3-(1-methylaminoethyl)pyrrolidinyl group,3-(1-dimethylamino-ethyl)pyrrolidinyl group;3-amino-3-methylpyrrolidinyl group, 3-amino-4-methylpyrrolidinyl group,3-amino-5-methylpyrrolidinyl group, 3-methylamino-4-methylpyrrolidinylgroup, 3-dimethylamino-4-methylpyrrolidinyl group,3-ethyl-amino-4-methylpyrrolidinyl group,3-diethylamino-3-methyl-pyrrolidinyl group,3-diethylamino-4-methylpyrrolidinyl group,3-aminomethyl-4-methylpyrrolidinyl group,3-methyl-aminomethyl-4-methylpyrrolidinyl group;3-dimethylaminomethyl-4-methylpyrrolidinyl group,3-ethyl-aminomethyl-4-methylpyrrolidinyl group,3-(1-aminoethyl)-4-methylpyrrolidinyl group,3-(2-aminoethyl)-4-methylpyrrolidinyl group, 3-amino-4-ethylpyrrolidinylgroup, 3-methylamino-4-ethylpyrrolidinyl group,3-dimethylamino-4-ethylpyrrolidinyl group,3-ethylamino-4-ethylpyrrolidinyl group,3-diethylamino-4-ethylpyrrolidinyl group,3-aminomethyl-4-ethylpyrrolidinyl group,3-methylaminomethyl-4-ethylpyrrolidinyl group;3-dimethylaminomethyl-4-ethylpyrrolidinyl group;3-amino-3-methylpyrrolidinyl group, 3-methylamino-3-methylpyrrolidinylgroup, 3-dimethylamino-3-methylpyrrolidinyl group,3-amino-3,4-dimethylpyrrolidinyl group, 3-amino-4,4-dimethylpyrrolidinyl group, 3-amino-4,5-dimethylpyrrolidinylgroup, 3-amino-2,4-dimethylpyrrolidinyl group,3-methylamino-3,4-dimethylpyrrolidinyl group;2-methyl-3-aminopyrrolidinyl group, 2-methyl-3-dimethylaminopyrrolidinylgroup, 3-amino-4-vinylpyrrolidinyl group, 3-amino-4-methoxypyrrolidinylgroup, 3-amino-4-methoxymethylpyrrolidinyl group,3-methylamino-4-methoxypyrrolidinyl group,3-dimethylamino-4-methoxypyrrolidinyl group,3-ethylamino-4-methoxypyrrolidinyl group,3-dimethylamino-4-methoxypyrrolidinyl group;3-benzylamino-4-methoxypyrrolidinyl group,3-aminomethyl-4-methoxypyrrolidinyl group,3-methylaminomethyl-4-methoxypyrrolidinyl group,3-dimethylaminomethyl-4-methoxypyrrolidinyl group,3-ethylaminomethyl-4-methoxypyrrolidinyl group,3-aminomethyl-3-methoxypyrrolidinyl group,3-methylaminomethyl-3-methoxypyrrolidinyl group,3-dimethylaminomethyl-3-methoxypyrrolidinyl group,3-amino-4ethoxypyrrolidinyl group, 3-methylamino-4-ethoxypyrrolidinylgroup, 3-dimethylamino-4-ethoxypyrrolidinyl group,3-methylamino-4-ethoxypyrrolidinyl group,3-aminomethyl-4-ethoxypyrrolidinyl group,3-dimethylaminomethyl-4-ethoxypyrrolidinyl group,3-amino-4-aminocarbamoylpyrrolidinyl group,3-amino-4-dimethylaminocarbamoylpyrrolidinyl group,3-amino-4-hydroxypyrrolidinyl group, 3-amino-4-hydroxymethylpyrrolidinylgroup, 3-amino-4-hydroxyethylpyrrolidinyl group;3-amino-4-methyl-4-hydroxymethylpyrrolidinyl group,3-aminomethyl-4-hydroxypyrrolidinyl group,3-dimethylaminomethyl-4-hydroxypyrrolidinyl group,3,4-dihydroxypyrrolidinyl group, 3,4-dimethoxypyrrolidinyl group, 3-hydroxy-4-methylpyrrolidinyl group, 3-amino-4-fluoropyrrolidinyl group,3-amino-4-fluoromethylpyrrolidinyl group,3-amino-4-trifluoromethylpyrrolidinyl group,3-methylamino-4-fluoropyrrolidinyl group,3-dimethylamino-4-fluoropyrrolidinyl group,3-aminomethyl-4-fluoropyrrolidinyl group,3-methylaminomethyl-4-fluoropyrrolidinyl group,3-dimethylaminomethyl-4-fluoropyrrolidinyl group;3-methylamino-4-chloropyrrolidinyl group;3-aminomethyl-4-chloropyrrolidinyl group,3-methylaminomethyl-4-chloropyrrolidinyl group, 3-(2-hydroxyethyl)aminomethylpyrrolidinyl group, 3-(2-fluoroethyl) aminometylpyrrolidinylgroup, 3-amino-4-methylthiopyrrolidinyl group,3-amino-4-methyl-sulfinylpyrrolidinyl group,3-formimidoylaminopyrrolidinyl group,3-(2-dimethylhydrazino)pyrrolidinyl group,3-amino-4-methylenepyrrolidinyl group, 3-(t-butoxycarbonylaminoacetyl)amino-4-methylpyrrolidinyl group,3-aminoacetylamino-4-methylpyrrolidinyl group,3-(2-aminopropanoyl)amino-4-methylpyrrolidinyl group,3-(2-amino-3-phenylpropanoyl)amino-4-methylpyrrolidinyl group,3-(2-benzyloxycarbonylamino-3-methylbutanoyl)amino-4-methylpyrrolidinylgroup,3-(2-amino-3-methylbutanoyl)amino-4-methylbutanoyl)amino-4-methylpyrrolidinylgroup, 3-(2-amino-2-methylpropanoyl)amino-4-methylpyrrolidinyl group,7-amino-5-azaspiro[2,4]heptan-5-yl group; piperazinyl group,4-methylpiperazinyl group, 3-methylpiperazinyl group,2-methylpiperazinyl group, 3,4-dimethylpiperazinyl group,3,5-dimethylpiperazinyl group, 3,3-dimethylpiperazinyl group,3,4,5-trimethylpiperazinyl group, 4-ethoxycarbonylpiperazinyl group,4-t-butoxycarbonylpiperazinyl group, 4-acetylpiperazinyl group,4-benzyloxycarbonylpiperazinyl group, 4-ethylpiperazinyl group,3,4-diethylpiperazinyl group, 3,4,5-triethylpiperazinyl group,4-ethyl-3,5-dimethylpiperazinyl group, 3-methyl-4-acetylpiperazinylgroup, 3-methyl-4-t-butoxycarbonylpiperazinyl group, 4-benzylpiperazinylgroup, 4-n-propylpiperazinyl group; 4-isopropylpiperazinyl group,4-t-butylpiperazinyl group, 4-cyclopyperazinyl group,4-cyclopentylpiperazinyl group, 4-cyclopropylmethylpiperazinyl group,4-phenylpiperazinyl group, 4-(p-dimethylaminophenyl)piperazinyl group,4-(p-methoxyphenyl)piperazinyl group, 4-(p-fluorophenyl)-piperazinylgroup, 3-phenylpiperazinyl group, 3-(p-fluorophenyl)piperazinyl group,3-(p-chlorophenyl)piperazinyl group, 3-(p-hydroxyphenyl)piperazinylgroup, 3-(p-methylphenyl)piperazinyl group, 4-hydroxyethylpiperazinylgroup; 4-aminoethylpiperazinyl group, 4-allylpiperazinyl group,4-cinnamylpiperazinyl group, 4-cyanoethylpiperazinyl group,4-carboxyethylpiperazinyl group, 4-carboxymethylpiperazinyl group,4-(1,2-dicarboxyethyl)piperazinyl group, 4-hydroxypiperazinyl group,3-fluoromethylpiperazinyl group, 3-trifluoromethylpiperazinyl group,4-formimidoylpiperazinyl group, 4-acetoimidoylpiperazinyl group;piperidino group, 4-amino piperidino group, 4-dimethylaminopiperidinogroup, 4-hydroxypiperidino group, morpholino group,2-aminomethylmorpholino group, 2-methylaminomorpholino group,2-dimethylaminomorpholino group, thiomorpholino group, homopiperazinylgroup, 4-methylhomopiperazinyl group, thiazolidinyl group, andoxazolidinyl group.

Examples of the cyclo- lower alkenyl group represented by Y includeunsaturated 5 to 7 membered aliphatic carbocyclic groups, such ascyclopentenyl group, cyclohexenyl group and cyclohexedienyl group.Examples of the cyclo- lower alkenyl groups represented by Y which mayhave a substituent include oxo-cyclohexenyl group, oxo-cyclopentenylgroup, amino-cyclohexenyl group and amino-cyclopentenyl group, amongwhich 3-oxo-cyclohexenyl group, 3-oxo-cyclopentenyl group,3-aminocyclohexenyl group and 3-amino-cyclopentenyl group are preferred.

In case where Y is the group represented by the formula R³ --(CH₂)_(m)--A--, groups similar to those capable of substituting the cyclic aminogroup described above may be mentioned as substitutable groups among theamino groups of R³ which may have a substituent.

In case where Z is the group represented by the formula C--R⁴, the atomssimilar to X may be mentioned as the halogen atoms represented by R⁴,among which fluorine atom and chlorine atom are preferred.

Example of the five-membered heterocyclic group represented by W whichhas 3 or more hetero atoms, among which at least 2 hetero-atoms arenitrogen atoms include saturated or unsaturated five-memberedheterocyclic group which has two nitrogen atoms and a hetero-atomselected from the group consisting of nitrogen, oxygen and sulfur. Theheterocyclic group represented by W may be substituted with a suitablesubstituent such as amino group, above-mentioned substituted aminogroup, oxo group or the like. Preferable examples of such substituentsare as follows: ##STR5##

Examples of the two kinds of substituents R⁵ and R⁶ in W individuallyinclude a hydrogen atom, a lower alkyl group similar to R², and halolower alkyl groups such as fluoromethyl trifluoromethyl and fluoroethyl.

Preferable examples of the group represented by W include:1,2,3-thiadiazole-4-yl, 5-methyl-1,2,3-thiadiazole-4-yl,1,3,4-thiadiazole-2-yl, 5-methyl-1,3,4-thiadiazole-2-yl,5-trifluoromethyl-1,3,4-thiadiazole-2-yl, 1,2,3-thiadiazole-5-yl,4-methyl-1,2,3-thiadiazole-5-yl, 1,2,4-thiadiazole-3-yl,5-methyl-1,2,4-thiadiazole-3-yl, 1,2,4-thiadiazole-5-yl,3-methyl-1,2,4-thiadiazole-5-yl, 1,2,5-thiadiazole-3-yl,4-methyl-1,2,5-thiadiazole-3-yl, 4-fluoromethyl-1,2,5-thiadiazole-3-yl,1,2,3-triazole-4-yl, 1-methyl-1,2,3-triazole-5-yl, 1,2,4-triazole-4-yl,3-methyl-1,2,4-triazole-4-yl, 1,2,4-triazole-3-yl,1-methyl-1,2,4-triazole-5-yl, 1-benzyl-1,2,4-triazole-3-yl,1,2,4-triazole-5-yl, 2-methyl-1,2,4-triazole-5-yl,2-benzyl-1,2,4-triazole-5-yl, 3,5-dimethyl-1,2,4-triazole-4-yl,1,2,3-oxadiazole-4-yl, 5-methyl-1,2,3-oxadiazole-4-yl,1,3,4-oxadiazole-2-yl, 5-methyl-1,3,4-oxadiazole-2-yl,5-trifluoromethyl-1,3,4-oxadiazole-2-yl, 1,2,3-oxadiazole-5-yl,4-methyl-1,2,3-oxadiazole-5-yl, 1,2,4-oxadiazole-3-yl,5-methyl-1,2,4-oxadiazole-3-yl, 1,2,4-oxadiazole-5-yl,3-methyl-1,2,4-oxadiazole-5-yl, 1,2,5-oxadiazole-3-yl,4-methyl-1,2,5-oxadiazole-3-yl, tetrazole- 5-yl,1-methyl-tetrazole-5-yl, 2-methyl-tetrazole-5-yl,1,2,5-thiadiazole-3-ylmethyl, and 1,2,3-thiadiazole-4-ylmethyl.

The quinolone derivatives or salts thereof of formula (1) can beconverted into both of acid addition salts and base addition salts, andthe salts include those forming chelate salts with boron compounds.Examples of acid addition salts include: (a) salts with mineral acidssuch as hydrochloric acid and sulfuric acid; (b) salts with organiccarboxylic acids such as formic acid, citric acid, trichloroacetic acid,trifluoroacetic acid, fumaric acid and maleic acid; and (c) salts withsulfonic acids such as methanesulfonic acid, benzenesulfonic acid,p-toluensulfonic acid, mesitylenesulfonic acid and naphthalenesulfonicacid. On the other hand, examples of base addition salts include: (a')salts with alkali metals such as sodium and potassium; (b') salts withalkaline earth metals such as calcium and magnesium; (c') ammoniumsalts; and (d') salts with nitrogen-containing organic bases such astrimethylamine, triethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,diethylamine, cyclohexylamine, procaine, dibenzylamine,N-benzyl-beta-phenethylamine, 1-ephenamine andN,N'-dibenzylethylenediamine. Examples of boron compounds include boronhalides such as boron fluoride, and lower acyloxy borons such as acetoxyboron,

The quinolone derivatives or salts thereof of formula (1) may be notonly in unsolvated forms but also in hydrated or solvated forms. Thepresent invention therefore embraces the compounds (1) in anycrystalline forms and their hydrated and solvated products.

The quinolone derivatives or salts thereof of formula (1) include thosecontaining an asymmetric carbon atom which can exist as optically activesubstances. These optically active substances are also embraced in thecompounds of the present invention. The compounds of formula (1) furtherinclude those containing two or more asymmetric carbon atoms which canexist as different stereoisomers (cis-form and trans-form). Thesestereoisomers are also included in the compounds of the presentinvention.

Each of the quinolone derivatives or salts thereof of formula (1) can beprepared by a process suited for the types of its substituent groups.Preferred preparation processes are as follows.

Process 1

Among the compounds represented by formula (1), those in which R¹ is ahydrogen atom or a lower alkyl group and Y is a halogen atom can beprepared, for example, by the series of steps shown in the followingreaction scheme (1): ##STR6## wherein X¹ and y¹ individually represent ahalogen atom; R^(1a) represents a lower alkyl group; R⁸ represents alower alkoxy group or a group ##STR7## wherein R¹¹ and R¹² individuallyrepresent a lower alkyl group; R⁹ and R¹⁰ individually represent a loweralkyl group; and X, Z, W, R² and n have the same meaning as definedabove.

Namely, the compound (C) can be obtained by reacting the compound (A)with an orthoformic acid ester (B) such as ethyl orthoformate or methylorthoformate in acetic anhydride, and then reacting the resultingproduct with the compound H₂ N--(CH₂)_(n) --W. The reaction between thecompound (A) and the orthoformic acid ester is conducted generally at0≧-160° C., preferably at 50°-150° C. The reaction time is generallyfrom 10 minutes to 48 hours, preferably from 1 hour to 10 hours. Theorthoformic acid ester (B) can be used in at least an equimolar amount,preferably in a molar amount about 1 to 10 times relative to thecompound (A).

The subsequent reaction with the compound H₂ N--(CH₂)_(n) --W isconducted in a suitable solvent. Any solvent can be used here, as longas it does not affect the reaction. Examples of such solvents include:aromatic hydrocarbons such as benzene, toluene and xylene; ethers suchas diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme;aliphatic hydrocarbons such as pentane, hexane, heptane and ligroin;halogenated hydrocarbons such as methylene chloride, chloroform andcarbon tetrachloride; dipolar aprotic solvents such as dimethylformamideand dimethylsulfoxide; and alcohols such as methanol, ethanol andpropanol. This reaction is conducted generally at 0°-150° C., preferablyat 0°-100° C. The reaction time generally ranges from 10 minutes to 48hours. The compound H₂ N--(CH₂)_(n) --W can be used in at least anequimolar amount, preferably in a molar amount 1-2 times relative to thecompound (A).

As an alternative, the compound (C) may be obtained by a reaction of thecompound (A) with an acetal such as N,N-dimethylformamide dimethylacetal or N,N-dimethylformamide diethyl acetal, followed by a reactionwith the compound H₂ N--(CH₂)_(n) --W. Any solvent may be used for thereaction with the acetal, as long as it is inert to the reaction. Theabovementioned solvents can be used as such inert solvent. This reactionis conducted generally at 0°-150° C., preferably at room temperature to100° C. The reaction time is generally from 10 minutes to 48 hours,preferably from 1 to 10 hours.

The compound (C) thus obtained is subjected to cyclization reaction toobtain compound (D). This reaction is conducted in a suitable solvent inthe presence of a basic compound. Any solvent can be used for thisreaction, as long as it does not affect the reaction. Examples of suchsolvents include: aromatic hydrocarbons such as benzene, toluene andxylene; ethers such as diethyl ether, tetrahydrofuran, dioxane andmonoglyme; halogenated hydrocarbons such as methylene chloride,chloroform and carbon tetrachloride; alcohols such as methanol, ethanol,propanol and butanol; dipolar aprotic solvents such as dimethylformamideand dimethylsulfoxide. Preferable examples of basic compounds include:alkali metals such as metallic sodium and metallic potassium; metalhydrides such as sodium hydride and calcium hydride; inorganic basessuch as sodium hydroxide, potassium hydroxide and sodium carbonate;alkoxides such as sodium methoxide, sodium ethoxide andpotassium-t-butoxide; metal fluorides such as potassium fluoride andsodium fluoride; and organic bases such as triethylamine and1,8-diazabicyclo [5.4.0]-undecene (DBU). This reaction is conductedgenerally at 0°-200° C., preferably from room temperature to 180° C. Thereaction can be brought to completion usually in 5 minutes to 24 hours.The basic compound may be used in at least an equimolar amount,preferably in a molar amount 1-2 times relative to the compound (c).

If desired, the compound (D) thus obtained is further subjected tohydrolysis to obtain compound (E). This reaction can be conducted underreaction conditions which are employed in usual hydrolysis reactions.For example, the hydrolysis reaction is carried out in the presence of abasic compound such as sodium hydroxide, potassium hydroxide, sodiumcarbonate or potassium carbonate; a mineral acid such as hydrochloricacid, sulfuric acid or hydrobromic acid; or an organic acid such asp-toluenesulfonic acid, and in a solvent, e.g. water; an alcohol such asmethanol, ethanol or propanol; an ether such as tetrahydrofuran ordioxane; a ketone such as acetone or methyl ethyl ketone; or an aceticacid; or a mixed solvent thereof. This reaction is conducted generallyat room temperature to 180° C., preferably from room temperature to 140°C. The reaction time generally ranges from 1 hour to 24 hours.

Process 2

Among the compounds represented by formula (1), those in which R¹ is ahydrogen atom or a lower alkyl group; and Y is a cyclic amino groupwhich may have a substituent, a cyclo lower alkenyl group which may havea substituent, or a group R³ --(CH₂)_(m) --A--, wherein R³, A and m havethe same meaning as defined above can be produced by the steps shown inthe following reaction scheme (2): ##STR8## wherein X^(1b) represents ahalogen atom or a lower alkyl group, y² is a cyclic amino group whichmay have a substituent, a cyclo lower alkenyl group which may have asubstituent or a group R³ --(CH₂)_(m) --A--, wherein R³, A and m havethe same meaning as defined above, and R², X, Y¹, W and n have the samemeaning as defined above.

Namely, the compound (F) obtained in the process 1 is reacted with thecompound represented by the formula Y² --H to obtain compound (G).

This reaction is carried out in a suitable solvent at room temperatureto 160° C., if desired, in the presence of an acid-neutralizing agentsuch as sodium carbonate, calcium carbonate, sodium hydrogencarbonate,triethylamine or 1,8-diazabicyclo [5.4.0]-undecene (DBU). Examples ofsolvents which are usable in this reaction include: aromatichydrocarbons such as benzene, toluene and xylene; alcohols such asmethanol and ethanol; ethers such as tetrahydrofuran, dioxane andmonoglyme; halogenated hydrocarbons such as methylene chloride,chloroform and carbon tetrachloride; dipolar aprotic solvents such asdimethylformamide and dimethylsulfoxide; and other solvents which do notadversely affect the reaction such as acetonitrile and pyridine. Thereaction can generally be brought to completion in a few minutes to 48hours, preferably from 10 minutes to 24 hours. The compound Y² --H maybe used in at least an equimolar amount, preferably in a molar amount1-5 times relative to the compound (F).

In cases where the R^(1b) of the compound (G) is a lower alkyl group,the group may be substituted with a hydrogen atom by hydrolysis.

When the starting compounds used in the processes 1 and 2 contain one ormore reactive groups which do not take part in the reactions, such asamino group, imino group, hydroxyl group, mercapto group or carboxylgroup, these starting compounds may be used in a form with these groupsbeing protected. In such case, the protective groups are removed in ageneral manner after the completion of the reaction. Any group can beused as the protective group, as long as it can be removed withoutdestroying the structure of the compound of the present invention to beformed by the reaction. Groups usually employed in the chemical field ofpeptides, aminosaccharides and nucleic acids can be used.

The starting compound (A) can be prepared by one of the processesdescribed in the following documents or by a similar process:

1) J. Heterocyclic Chem. 2.2, 1033 (1985)

2) Liebigs Ann. Chem. 29 (1987)

3) J. Med. Chem. 31, 911 (1988)

4) J. Org. Chem. 35, 930 (1970)

5) Japanese Patent Application Laid-open (Kokai) No. 246541/1987

6) Japanese Patent Application Laid-open (Kokai) No. 26272/1987

7) Japanese Patent Application Laid-open (Kokai) No. 145268/1988

8) J. Med. Chem. 29, 2363 (1986)

9) J. Fluorin Chem. 28, 361 (1985)

10) Japanese Patent Application Laid-open (Kokai) No. 198664/1988

11) Japanese Patent Application Laid-open (Kokai) No. 264461/1988

12) Japanese Patent Application Laid-open (Kokai) No. 104974/1988

13) European Patent Application No. 230948

14) Japanese Patent Application Laid-open (Kokai) No. 282384/1990

15) Japanese Kohyo Publication No. 502452/1991

16) J. Het. Chem. 27, 1609 (1990)

Process 3

Among the compounds represented by formula (1), those in which R¹ is acarboxy protective group can be prepared by the steps shown in thefollowing reaction scheme (3): ##STR9## wherein R^(1c) represents acarboxy protective group, X² represents a halogen atom, and R², X, Y, Z,W and n have the same meaning as defined above.

Compound (I) is obtained by reacting the compound (H) with the halogencompound R^(1c) --X². Examples of the preferred solvents include:aromatic hydrocarbons such as benzene and toluene; halogenatedhydrocarbons such as methylene chloride and chloroform; dipolar aproticsolvents such as dimethylformamide and dimethyl sulfoxide; and otherinactive solvents such as acetonitrile. The reaction is carried out atroom temperature to 100° C. It is preferred that this reaction becarried out in the presence of a basic compound such as triethylamine,diisopropylethylamine, dicyclohexylamine, DBU, sodium carbonate,potassium carbonate or sodium hydroxide.

Among the compounds represented by the formula (1), those containing aprimary or secondary amino group as heterocyclic group indicated by Ycan be converted to the compounds which have a formimidoyl group orlower alkylimdoyl group on the amino group by reacting with formimidicacid ester or lower alkanecarboximidic acid ester.

The compounds of the present invention thus obtained are isolated andpurified by methods known per se in the art. They are obtained in theform of salts, free carboxylic acids or free amines, depending on theconditions for isolation and purification. However, they can beconverted mutually from one of these forms into another one, whereby thecompounds of the present invention can be prepared in a desired form.

When the compounds (1) of the present invention are used asantibacterial agents, the compositions can be treated as compositionstogether with pharmaceutical allowable carriers for parenteral dosagesuch as injection, per rectum, eye instillation and the like and oraladministration in the form of solid and solution.

Relating to the form of the composition for injection, pharmaceuticalallowable axenic water or nonaqueous solution, suspension or emulsionand the like are give. As examples of appropriate nonaqueous carrier,diluent, solution or vehicle, propylene glycol, polyethylene glycol andvegetable oils such as olive oil and injectable organic estersincluding, for example, oleic acid ethyl are given. There compositionsmay include supplementary agents such as antiseptics, wetting agents,emulsifiers, dispersants and the like. The compositions, for example,can be sterilized by filtering with a bacteria holding filter or bymixing with a sterilizer in the form of an axenic solid compositionsoluble in sterilized water or other several sterilized injectablesolutes or media right before the use.

The preparation for eye instillation dosage can preferably includedissolution adjuvants, preservatives, isotonic agents, mucilages and thelike.

The solid preparations for oral dosage can include capsules, tablets,pills, powders and granules. In preparing the solid preparations,generally, the compound of the present invention is mixed with at leastone kind of an inert diluent such as sucrose, lactose or starch. In ausual preparation, the preparations can further include a supplementarymaterial except the inert diluent, for example, a lubricant such asmagnesium stealate or the like. Further, the capsules, tablets and pillscan further include a buffer. The tablets and pills can further apply anenteric coat thereon.

The solution preparations for oral dosage can include inert diluentsusually used by a person skilled in the art, for instance,pharmaceutical allowable emulsifiers including water, solutions,suspensions, syrups and elixirs. In addition to such inert diluents, thecompositions can be blended with supplementary agents such as wettingagents, emulsifiers, suspensions, edulcorants, flavors and perfumes.

The preparations for per rectum dosage may preferably include excipientssuch as cocoa butter or suppository wax in addition to the compound ofthe present invention.

The dose of the compound represented by general formula (1) depends onthe properties of the compound to be dosed, dosing route, the desiredtreating period and other factors, and is, in general, approximately 0.1to 1000 mg/kg a day, and preferably approximately 1 to 100 mg/kg a day.If necessary, this dose for one day can be divided into 2-4 times.

EXAMPLE 1 Ethyl3-(1,2,5-thiadiazol-3-yl-amino)-2-(2,6-dichloro-5-fuluoronicotinoyl)acrylate(Compound No.1)

A mixture of ethyl 2,6-dichloro-5-fluoronicotinoylacetate (5.4 g),triethyl orthoformate (4.8 ml) and acetic anhydride (5.5 ml) was stirredat 130° C. for 2 hours. After the solvent was removed in vacuo, asolution of 3-amino-1,2,5-thiadiazole hydrochloride (2.75 g) andtriethylamine (2 g) in chloroform (20 ml) was added to the residue. Themixture was stirred at room temperature for 20 hours. The solvent wasremoved in vacuo. The residue was purified by chromatography onsilicagel (chloroform as an eluent). The title compound No. 1 wasobtained as a yellow oil (6.8 g).

¹ H-NMR(CDCl₃) δ; 0.96 and 1.17(t,J=7 Hz,3H), 4.16(q,J=7 Hz,2H), 7.43and 7.56(d,J=7 Hz,1H), 8.33 and 8.38(s,1H), 8.95 and 9.03(d,J=12.5Hz,1H)

EXAMPLE 2 Ethyl7-chloro-6-fluoro-1(1,2,5-thiadiazol-3-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate(Compound No.2)

To a solution of compound No. 1 (6.8 g) in tetrahydrofuran (200 ml), 0.7g of sodium hydride (60% in oil) was added with ice cooling. Then thesolution was stirred for 1 hour at the same temperature. After additionof aqueous 5% citric acid solution (50 ml), tetrahydrofuran was removedin vacuo. The aqueous solution was extracted with chloroform (200 ml).The organic phase was washed with water, dried over Na₂ SO₄ andevaporated under reduced pressure. To the residue was addeddiisopropylether and filtrated. The title compound No. 2 was obtained asa yellow solid (5.2 g).

Melting point: 175°-178° C. ¹ H-NMR(CDCl₃) δ; 1.43(t,J=7 Hz,3H),4.43(q,J=7 Hz,2H), 8.54(d,J=6.9 Hz,1H), 9.26(s,1H), 9.27(s,1H)

EXAMPLE 37-Chloro-6-fluoro-1-(1,2,5-thiadiazol-3-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (Compound No.3)

Compound No.2 (5 g) was dissolved in acetic acid (50 ml) and 6N-HCl (20ml). The solution was stirred at 100° C. for 0.5 hour. After cooling,the precipitate was filtrated and washed with water, ethanol and ether.The title compound No. 3 was obtained as pale yellow needles (4.5 g).

Melting point: 222°-223° C. ¹ H-NMR(DMSO-d₆) δ; 8.8(d,J=7.8 Hz,1H),9.24(s,1H), 9.26(s,1H)

EXAMPLE 4 6-Fluoro-7-(pyrrolidin-1-yl)-1-(1,2,5-thiadiazole-3-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (Compound No.4)

A mixture of compound No.3 (80 mg), pyrrolidine (21 mg) andtriethylamine (50 mg) in acetonitrile (5 ml) was stirred at 80° C. for30 minutes. After cooling, the precipitate was filtrated and washed withethanol and diisopropylether successively. The title compound No. 4 wasobtained as a pale yellow solid (85 mg).

Melting point: 269°-273° C. ¹ H-NMR(CDCl₃) δ; 1.9-2.1(m,4H),3.7(brs,4H), 8.0(d,J=12.8 Hz,1H), 9.12(s,1H), 9.18(s,1H)

EXAMPLE 5

Compounds Nos. 5-11 listed in Tables 1 and 2 were prepared in a similarmanner to Example 4. The data are also shown in Tables 1-2.

                                      TABLE 1                                     __________________________________________________________________________    Compound:                                                                      ##STR10##                                                                            Group                                                                 Compound No.                                                                          R.sup.2                                                                         Y       Z Property                                                                             Melting point (°C.)                                                              .sup.1 H-NMR        Solvent              __________________________________________________________________________    5       H                                                                                ##STR11##                                                                            N Pale yellow solid                                                                    274  ∫ 276                                                                         [CDCl.sub.3 +DMSO-d.sub.6 ] δ;                                          .25-4.45(m, 2H), 4.65-4.85(m, 2H),                                            5.95(s, 2H), 8.1(d, J=12.4Hz, 1H),                                            9.17(s, 1H), 9.18(s,                                                                              CH.sub.3 CN          6       H                                                                                ##STR12##                                                                            N Colorless solid                                                                      254  ∫  257                                                                        [CDCl.sub.3 +DMSO-d.sub.6 ] δ;                                          .65-3.85(m, 8H), 8.15(d, J=13.3Hz,                                            1H), 9.03(s, 1H), 9.11(s,                                                                         CH.sub.3 CN          7       H                                                                                ##STR13##                                                                            N Pale yellow solid                                                                    244  ∫ 246                                                                         [CDCl.sub.3 ] δ; 2.65-2.8(m,                                            4H), 4.0-4.1(m, 4H), 8.15(d,                                                  J=13.3Hz, 1H), 9.0(s, 1H), 9.1(s,                                             1H)                 CH.sub.3             __________________________________________________________________________                                                             CN               

                                      TABLE 2                                     __________________________________________________________________________            Group                                                                 Compound No.                                                                          R.sup.2                                                                         Y         Z Property                                                                             Melting point (°C.)                                                              .sup.1 H-NMR      Solvent              __________________________________________________________________________     8      H                                                                                ##STR14##                                                                              N Red solid                                                                            288  ∫ 292                                                                         [DMSO-d.sub.6 ] δ; 2.85-3.0(m                                           , 2H), 3.8-3.9(m, 2H), 7.47(s,                                                1H), 8.19(d, J=12.4Hz, 1H),                                                   9.06(s, 1H), 9.4(s,                                                                             CH.sub.3 CN           9      H                                                                                ##STR15##                                                                              N Pale yellow solid                                                                    233  ∫ 236                                                                         [DMSO-d.sub.6 ] δ; 7.22(s,                                              1H), 7.74(s, 1H), 8.39(s, 1H),                                                8.88(d, J=10.2Hz, 1H), 9.23(s,                                                1H), 9.4(s, 1H)   CH.sub.3 CN          10      H                                                                                ##STR16##                                                                              N Colorless solid                                                                      238.5  ∫  239.5                                                                    [DMSO-d.sub.6 ] δ; 3.05-3.2(m                                           , 2H), 3.92(brs, 2H), 4.73(s, 2H),                                            8.17(d, J=12.8Hz, 1H), 9.0(s, 1H),                                            9.35(s, 1H)       CH.sub.3 CN          11      H                                                                                ##STR17##                                                                              N Pale ocher solid                                                                     217  ∫ 219                                                                         [DMSO-d.sub.6 ] δ; 1.91(brs,                                            2H), 4.36(brs, 1H), 5.09(brs, 1H),                                            8.04(d, J=12.7Hz, 1H), 8.96(s,                                                1H), 9.33(s, 1H)  CH.sub.3 CN                                                                   ET.sub.3             __________________________________________________________________________                                                             N                

EXAMPLE 66-Fluoro-7-(7-amino-5-azaspiro[2.4]heptan-5-yl)-1-(1,2,5-thiadiazol-3-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid hydrochloride (Compound No.12)

A mixture of compound No.3 (114 mg), triethylamine (70 mg) and7-t-buthoxycarbonylamino-5-azaspiro[2.4]heptane (90 mg) in acetonitrile(5 ml) was stirred at 80° C. for 10 minutes. After the solvent wasremoved in vacuo, the residue was extracted with chloroform (50 ml). Theorganic layer was washed with 5% aqueous citric acid solution and watersuccessively, then dried. After the solvent was removed in vacuo,4N-HCl/1,4-dioxane (5 ml) was added to the residue. The solution wasstirred at room temperature for 1 hour. The precipitate was collected byfiltration. The title compound No. 12 was obtained as a yellow solid(110 mg).

Melting point: 216°-221.5° C. ¹ H-NMR(DMSO-d₆ ) δ; 0.7-1.0(m,3H),1.0-1.2(m,1H), 3.8-4.4(m,3H), 8.16(d,J=12.2 Hz,1H), 8.35(brs,3H),9.0(s,1H), 9.36(s,1H)

EXAMPLE 7

Compounds Nos. 13 and 14 listed in Table 3 were prepared in a similarmanner to Example 6. The results are also shown in Table 3.

                                      TABLE 3                                     __________________________________________________________________________    Compound:                                                                      ##STR18##                                                                            Group                                                                 Compound No.                                                                          R.sup.2                                                                         Y          Z Property                                                                           Melting point (°C.)                                                              .sup.1 H-NMR       Solvent              __________________________________________________________________________    13      H                                                                                ##STR19## N Yellow solid                                                                       215  ∫ 220.5                                                                       [DMSO-d.sub.6 ] δ; 0.7-1.0(m,                                           3H), 1.0-1.2(m, 1H), 3.7-4.4(m,                                               3H), 8.16(d, J=12.4Hz, 1H),                                                   8.25(brs, 3H), 9.0(s, 1H), 9.36(s,                                            1H)                                                                                               ##STR20##           14      H                                                                                ##STR21## N Yellow solid                                                                       217  ∫ 224                                                                         [DMSO-d.sub.6 ] δ; 0.7-1.0(m,                                           3H), 1.0-1.2(m, 1H), 3.7-4.3(m,                                               3H), 8.16(d, J=12.2Hz, 1H),                                                   8.37(brs, 3H), 9.0(s, 1H), 9.36(s,                                            1H)                                                                                               ##STR22##           __________________________________________________________________________

EXAMPLE 86-Fluoro-7-(2-aminoethylthio)-1-(1,2,5-thiadiazole-3-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid hydrochloride (Compound No.15)

A mixture of compound No.3 (100 mg), triethylamine (60 mg) and2-t-buthoxycarbonylaminoethanethiol (71 mg) in acetonitrile (5 ml) wasstirred at room temperature for 30 minutes. The precipitate wascollected by filtration and dissolved in acetic acid (1 ml) and 6N-HCl(1ml). After stirring at 100° C. for 20 minutes, 5 ml of water was addedto this solution. The precipitate was collected by filtration and washedwith ethanol, chloroform and ether successively. The title compound No.15 was obtained as a colorless solid (70 mg).

Melting point: Colored and decomposed at 269° C. or more ¹H-NMR(DMSO-d₆) δ; 2.84(brs,2H), 3.3(brs,2H), 8.14(brs,3H), 8.47(d,J=9.0Hz,1H), 9.19(s,1H), 9.33(s,1H)

EXAMPLE 97-(3-Amino-1-cyclohexen-1-yl)-6-fluoro-1-(1,2,5-thiadiazol-3-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacidhydrochloride (Compound No.16)

The compound No.2 (200 mg) obtained in Example 2,bistriphenylphosphine-palladium(II)chloride (10 mg) and2,6-di-t-butyl-4-methylphenol (2 pieces of crystal) were dissolved inN,N-dimethylformamide (2 ml). 300 mg of3-t-buthoxycarbonylamino-1-tri-n-butylstannyl-1-cyclohexene were addedthereto at 85° C. during 20 minutes. After stirring at 100° C. for 1.5hours, the solvent was removed, the residue was added with hexane (10ml) and filtrated. The collected solid matter was purified bychromatography on silicagel(chloroform/ethylacetate 10:1). The paleyellow solid (100 mg) which was obtained was dissolved in a mixture ofacetic acid (1 ml) and 6N-HCl (1 ml), then this solution was stirred at100° C. for 30 minutes. After evaporation of the solvent, 5 ml ofethanol was added. The precipitate was collected by filtration andwashed with diisopropylether. The title compound No. 16 was obtained asa yellow solid (30 mg).

Melting point: Colored and decomposed at 235° C. or more ¹H-NMR(DMSO-d₆) δ; 1.5-1.8(m,2H), 1.8-2.1(m,2H), 2.36(brs,2H),4.04(brs,1H), 6.8(s,1H), 8.35(brs,3H), 8.63(d,J=10.7 Hz,1H),9.25(brs,2H)

EXAMPLE 10

Compound No.17 listed in Table 4 was synthesized in a similar manner toExample 9. The data are also shown in Table 4.

                                      TABLE 4                                     __________________________________________________________________________    Compound:                                                                      ##STR23##                                                                            Group                                                                 Compound No.                                                                          R.sup.2                                                                         Y      Z Property                                                                             Melting point (°C.)                                                              .sup.1 H-NMR         Soluent              __________________________________________________________________________    17      H                                                                                ##STR24##                                                                           N Yellow solid                                                                         188  ∫ 195                                                                         [CDCl.sub.3 ] δ; 2.1-2.3(m,                                             2H), 2.5-2.65(m, 2H), 2.7-2.8(m, 2H),                                         6.84(s, 1H), 8.6(d, J=9.8Hz, 1H),                                             9.12(s, 1H), 9.46(s,                                                                               DMF                  __________________________________________________________________________

EXAMPLE 117-(3-(S)-Aminopyrrolidin-1-yl)-6-fluoro-1-(1,2,5-thiadiazol-3-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid hydrochloride (Compound No.18)

A mixture of compound No.3 (1.5 g), triethylamine (1.06 g) and3-(S)-aminopyrrolidine (0.46 g) in acetonitrile (150 ml) was stirred at80° C. for 60 minutes. After cooling, the precipitate was filtrated andwashed with ethanol (5 ml), then dissolved in 10 ml of c-HCl and stirredfor 10 minutes. After the solvent was evaporated, ethanol (10 ml) wasadded for filtration. A yellow solid of the title compound was obtained(1.6 g). Crystallization from ethanol-water yielded the title compoundNo. 18 in pale yellow needles (1.5 g).

Melting point: Colored from 235° C., and melted at 257°-260° C. ¹H-NMR(DMSO-d₆) δ; 2.5(brs,1H), 2.51(brs,1H), 8.13(d,J=12.7 Hz,1H),8.0-8.8(br,3H), 9.00(s,1H), 9.33(s,1H)

EXAMPLE 12

Compounds Nos. 19-31 listed in Tables 5-8 were synthesized in a similarmanner to Example 11. The data are also shown in Tables 5-8.

                                      TABLE 5                                     __________________________________________________________________________    Compound:                                                                      ##STR25##                                                                            Group                                                                 Compound No.                                                                          R.sup.2                                                                         Y           Z Property                                                                            Melting point (°C.)                                                              .sup.1 H-NMR      Solvent             __________________________________________________________________________    19      H                                                                                ##STR26##  N Pale yellow needles                                                                 241  ∫ 243                                                                         [DMSO-d.sub.6 ] δ; 1.10(d,                                              J=6.8Hz, 3H), 2.5-2.7(m, 1H),                                                 8.13(d, J=12.7Hz, 1H), 8.4(brs,                                               3H), 8.99(s, 1H), 9.35(s,                                                                       MeCN Et.sub.3                                                                 N                   20      H                                                                                ##STR27##  N Pale ocher solid                                                                    255  ∫ 260                                                                         [DMSO-d.sub.6 ] δ; 1.26(d,                                              J=6.4Hz, 3H), 1.70(brs, 1H),                                                  2.04(brs, 1H), 2.45(brs, 1H),                                                 8.07(d, J=12.7Hz, 1H), 8.23(brs,                                              3H), 8.97(s, 1H), 9.36(s,                                                                       MeCN Et.sub.3       __________________________________________________________________________                                                              N               

                                      TABLE 6                                     __________________________________________________________________________    Compound                                                                             Group                                                                  No.    R.sup.2                                                                         Y           Z Property                                                                             Melting point (°C.)                                                              .sup.1 H-NMR      Solvent             __________________________________________________________________________    21     H                                                                                ##STR28##  N Pale yellow solid                                                                    257  ∫ 259                                                                         [DMSO-d.sub.6 ] δ; 1.46(s,                                              3H), 2.09(brs, 1H), 2.25(brs,                                                 1H), 8.14(d, J=12.2Hz, 1H),                                                   9.00(s, 1H), 9.36(s,                                                                            MeCN Et.sub.3                                                                 N                   22     H                                                                                ##STR29##  N Pale orange solid                                                                    207  ∫ 213                                                                         [DMSO-d.sub.6 ] δ; 0.93(d,                                              J=6.35Hz, 3H), 2.91(brs, 2H),                                                 8.10(brs, 1H), 8.0-8.9(br, 3H),                                               8.98(s, 1H), 9.42(s,                                                                            MeCN Et.sub.3                                                                 N                   23     H                                                                                ##STR30##  N Pale yellow solid                                                                    250  ∫ 260 Decomposed                                                              [DMSO-d.sub.6 ] δ; 3.8-4.0(m                                            , 2H), 8.16(d, J=11.2Hz, 1H),                                                 8.62(brs, 3H), 9.03(s, 1H),                                                   9.30(s, 1H)       MeCN Et.sub.3                                                                 N                   24     H                                                                                ##STR31##  N Pale yellow solid                                                                    268  ∫ 275 Decomposed                                                              [DMSO-d.sub.6 ] δ; 3.48(s,                                              4H), 3.86(s, 4H), 8.27(d,                                                     J=13.2Hz, 1H), 9.04(s, 1H),                                                   9.32(s, 1H), 9.1-9.8(br,                                                                        MeCN Et.sub.3       __________________________________________________________________________                                                              N               

                                      TABLE 7                                     __________________________________________________________________________            Group                                                                 Compound No.                                                                          R.sup.2                                                                         Y         Z Property                                                                             Melting point (°C.)                                                              .sup.1 H-NMR      Solvent              __________________________________________________________________________    25      H                                                                                ##STR32##                                                                              N Pale yellow solid                                                                    Colored from 240° C., decomposed                                                 [DMSO-d.sub.6 +D.sub.2 O] δ;                                            .82(s, 3H), 8.24(d, J=13.2Hz, 1H),                                            .01(s, 1H), 9.27(s,                                                                             CH.sub.3 CN                                                                   Et.sub.3 N           26      H                                                                                ##STR33##                                                                              N Colorless solid                                                                      Colored from 268° C., decomposed                                                 [DMSO-d.sub.6 ] δ; 1.2(d,                                               J=6.4Hz, 3H), 3.0-3.15(m, 1H),                                                3.45-3.6(m, 1H), 4.1-4.3(m, 2H),                                              8.27(d, J=13.2Hz, 1H), 9.04(s,                                                1H), 9.31(s, 1H), 9.4-9.7(br,                                                                   CH.sub.3 CN                                                                   Et.sub. 3 N          27      H                                                                                ##STR34##                                                                              N Colorless solid                                                                      251  ∫ 253                                                                         [DMSO-d.sub.6 ] δ; 3.1-3.3(m,                                            2H), 3.5-3.8(m, 2H), 4.15-4.32(m,                                            2H), 4.6(brs, 1H), 4.8(brs, 1H),                                              8.3(d, J=13.2Hz, 1H), 9.05(s, 1H),                                            9.32(s, 1H), 9.9(brs,                                                                           CH.sub.3 CN                                                                   Et.sub.3 N           28      H                                                                                ##STR35##                                                                              N Colorless solid                                                                      Colored from 292° C., decomposed                                                 [DMSO-d.sub.6 ] δ; 1.22(d,                                              J=7.3Hz, 6H), 3.15-3.5(m, 4H),                                                4.22(d, J=12.7Hz, 2H), 8.27(d,                                                J=12.7Hz, 1H), 9.05(s, 1H),                                                   9.32(s, 1H), 9.7(brs,                                                                           CH.sub.3 CN                                                                   Et.sub.3             __________________________________________________________________________                                                             N                

                                      TABLE 8                                     __________________________________________________________________________             Group                                                                Compound No.                                                                           R.sup.2                                                                         Y        Z Property                                                                             Melting point (°C.)                                                              .sup.1 H-NMR       Solvent             __________________________________________________________________________    29       H                                                                                ##STR36##                                                                             N Pale yellow solid                                                                    Colored from 259° C., decomposed                                                 [DMSO-d.sub.6 ] δ; 1.9-2.2(m,                                            2H), 4.48(s, 1H) 8.2(d, J=12.2Hz,                                            1H), 9.01(s, 1H), 9.26(brs, 1H),                                              9.31(s, 1H), 9.71(brs,                                                                           CH.sub.3 CN                                                                   Et.sub.3 N          30       H                                                                                ##STR37##                                                                             N Colorless solid                                                                      Colored from 277° C., decomposed                                                 [DMSO-d.sub.6 ] δ; 2.0-2.2(br                                           s, 1H), 2.3-2.5(brs, 1H), 2.83(s,                                             3H), 3.05-3.2(m, 1H), 3.6-3.9(br,                                             1H), 4.44(s, 1H), 8.20(d,                                                     J=12.2Hz, 1H), 9.0(s, 1H), 9.33(s,                                            1H), 11.1(brs, 1H) CH.sub.3 CN                                                                   Et.sub.3 N          31       H                                                                                ##STR38##                                                                             N Colorless solid                                                                      Colored from 278° C., decomposed                                                 [DMSO-d.sub.6 ] δ; 1.8-2.9(m,                                            4H), 3.5-3.6(m, 2H), 4.0-4.15(m,                                             4H), 8.26(d, J=13.2Hz, 1H),                                                   9.03(s, 1H), 9.30(s, 1H),                                                     9.4-9.9(br, 1H)    CH.sub.3 CN                                                                   Et.sub.3            __________________________________________________________________________                                                              N               

EXAMPLE 13 Ethyl3-(1,2,5-thiadiazol-3-yl-amino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylate(Compound No.32)

A mixture of ethyl 2,3,4,5-tetrafluorobenzoylacetate(2.64 g), ethylorthoformate(2.5 ml) and acetic anhydride(2.8 ml) was stirred at 130° C.for 6 hours. After the solvent was removed in vacuo, a solution of3-amino-1,2,5-thiadiazole hydrochloride (1.38 g) and triethylamine(1 g)in benzene(20 ml) was added to the residue. The mixture was stirred atroom temperature for 2 hours. The solvent was removed in vacuo. Theresidue was purified by chromatography on silicagel(chloroform/ethylacetate 50:1 as an eluent). The title compound NO. 32 was obtained as ayellow solid (3.7 g).

Melting point: 81°-83° C. ¹ H-NMR(CDCl₃) δ;1.06 and 1.22 (t,J=7 Hz,3H)4.15 and 4.18 (q,J=7 Hz,2H) 7.05-7.2 and 7.25-7.4 (m,1H) 8.31 and 8.36(s,1H) 8.74 and 8.95 (d,J=12.2 Hz,1H)

EXAMPLE 14 Ethyl1-(1,2,5-thiadiazol-3-yl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.33)

To a solution of compound No.32 (3.7 g) in tetrahydrofuran (100 ml), 0.4g of sodium hydride (60% in oil) was added with ice cooling over 20minutes. Then the solution was stirred for 20 minutes at roomtemperature. After addition of 5% aqueous citric acid solution (10 ml),tetrahydrofuran was removed in vacuo. The aqueous solution was extractedwith chloroform (100 ml). The organic phase was washed with water, dried(MgSO₄) and evaporated. The residue was added with diisopropylether andthe solid matter was collected by filtration. The title compound No. wasobtained as a colorless solid (2.7 g).

Melting point: 167°-169° C. ¹ H-NMR(CDCl₃) δ; 1.39(t,J=7 Hz, 3H),4.39(q,J=7 Hz, 2H), 8.1-8.25(m,1H), 8.48(s,1H), 8.72(s,1H)

EXAMPLE 151-(1,2,5-Thiadiazol-3-yl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.34)

Compound No.33 (2.7 g) was dissolved in acetic acid (25 ml) and 6N-HCl(10 ml). The solution was stirred at 100° C. for 0.5 hour. Aftercooling, the precipitate was filtrated and washed with water, ethanoland ether successively. The title compound No. 34 was obtained as acolorless solid (2.3 g).

Melting point: 205°-207° C. ¹ H-NMR(DMSO-d₆) δ; 8.15-8.3(m,1H),9.07(s,1H), 9.23(s,1H)

EXAMPLE 16

Compounds Nos. 35-39 listed in Tables 9 and 10 were prepared in asimilar manner to Example 11, starting from compound No.34 and indicatedamines. The results are shown in Tables 9 and 10.

                                      TABLE 9                                     __________________________________________________________________________    Compound:                                                                      ##STR39##                                                                    Compound                                                                            Group                                                                   No.   R.sup.2                                                                         Y          Z Property                                                                             Melting point (°C.)                                                              .sup.1 H-NMR       Solvent              __________________________________________________________________________    35    H                                                                                ##STR40##                                                                                ##STR41##                                                                      Ocher solid                                                                          206  ∫ 212                                                                         [DMSO-d.sub.6 ] δ; 1.92-2.09(m                                          , 1H), 2.09-2.27(m, 1H), 3.6-4.0(m,                                           4H), 7.85(d, J=13.7Hz, 1H).                                                   8.42(brs, 3H), 8.90(s, 1H), 9.22(s,                                           1H)                MeCN Et.sub.3 N      36    H                                                                                ##STR42##                                                                                ##STR43##                                                                      Pale yellow solid                                                                    231  ∫ 234                                                                         DMSO-d.sub.6 ] δ; 1.04(d,                                               J=6.8Hz, 3H), 2.4-2.6(m, 1H),                                                 3.5-4.1(m, 4H), 7.85(d, J=13.7Hz,                                             1H), 8.0-8.75(br, 3H), 8.90(s, 1H),                                           .22(s, 1H)         MeCN Et.sub.3        __________________________________________________________________________                                                             N                

                                      TABLE 10                                    __________________________________________________________________________    Compound                                                                      No.   R.sup.2                                                                         Y          Z Property                                                                             Melting point (°C.)                                                              .sup.1 H-NMR       Solvent              __________________________________________________________________________    37    H                                                                                ##STR44##                                                                                ##STR45##                                                                      Pale yellow solid                                                                    268  ∫ 275 decomposed                                                              [DMSO-d.sub.6 ] δ; 3.15(brs,                                            4H), 3.46(brs, 4H), 8.00(d,                                                   J=11.7Hz, 1H), 8.98(s, 1H), 9.23(s,                                           1H), 9.43(brs, 1H), 9.73(brs,                                                                    MeCN Et.sub.3 N      38    H                                                                                ##STR46##                                                                                ##STR47##                                                                      Pale yellow solid                                                                    244  ∫ 250 decomposed                                                              [DMSO-d.sub.6 ] δ; 2.77(s,                                              3H), 3.53(s, 4H), 7.98(d, J=11.7Hz,                                           1H), 8.98(s, 1H), 9.23(s, 1H),                                                11.0-11.3(br, 1H)  MeCN Et.sub.3 N      39    H                                                                                ##STR48##                                                                                ##STR49##                                                                      Pale yellow solid                                                                    Colored from  200° C., decomposed                                                [DMSO-d.sub.6 ] δ; 3.8-4.0(m,                                           2H), 7.90(d, J=12.7Hz, 1H),                                                   8.38(brs, 3H), 8.92(s, 1H), 9.22(s,                                           1H),               MeCN Et.sub.3        __________________________________________________________________________                                                             N                

EXAMPLE 17 Ethyl2-(2,4,5-trifluorobenzoyl)-3-(1,2,5-thiadiazol-3-ylamino)acrylate(Compound No.40)

A mixture of ethyl 2,4,5-trifluorobenzoylacetate(8.94 g), ethylorthoformate(8.09 g) and acetic anhydride(16.7 g) was stirred at 130° C.for 3 hours. After the solvent was removed in vacuo, a solution of3-amino-1,2,5-thiadiazole hydrochloride (5.0 g) and triethylamine (3.68g) in benzene(50 ml) was added to the residue. The mixture was stirredat room temperature for 1 night. The solvent was evaporated and theresidue was purified by chromatography on silicagel(chloroform as aneluent). The title compound No. 40 was obtained as a colorless solid(10.4 g).

Melting point: 117°-118° C. ¹ H-NMR(CDCl₃) δ; 1.04 and 1.19 (t,J=7Hz,3H), 4.09-4.26(m,2H), 6.88-7.01(m,1H), 7.31-7.42 and 7.47-7.61(m,1H),8.28 and 8.33(s,1H) 8.68 and 8.91(d,J=12.5 Hz,1H)

EXAMPLE 18 Ethyl6,7-difluoro-1-(1,2,5-thiadiazol-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.41)

To a solution of compound No.40 (1.6 g) in tetrahydrofuran (50 ml), 0.22g of sodium hydride (60% in oil) was added at room temperature for 1hour. After addition of 5% aqueous citric acid solution, tetrahydrofuranwas removed in vacuo. The aqueous solution was extracted with chloroform(50 ml). Evaporation was carried out after drying over Na₂ SO₄). Theresidue was purified by chromatography on silicagel (chloroform as aneluent). The title compound No. 41 was obtained as a colorless solid(1.13 g).

Melting point: 189°-192° C. ¹ H-NMR(DMSO-d₆) δ; 1.28(t,J=7 HZ,3H),4.25(q,J=7 HZ,2H), 7.69(dd,J=6.5 HZ,J=12 Hz,1H), 8.14(dd,J=10.3 Hz,J=8.8Hz,1H), 8.81(s,1H),9.25(s,1H)

EXAMPLE 196,7-Difluoro-1-(1,2,5-thiadiazol-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.42)

Compound No.41 (6.9 g) was dissolved in acetic acid (100 ml) and c-HCl(25 ml). The solution was stirred at 100° C. for 1 hour. Afterevaporation of the solvent, 50 ml of chloroform was added. Theprecipitate was filtrated and washed with diethylether (30 ml). Thetitle compound No. 42 was obtained as a colorless solid (6.0 g).

Melting point: 255-256.5° C. ¹ H-NMR(DMSO-d₆) δ; 7.86(dd,J=11.7 Hz,J=6.8Hz,1H), 8.36(dd,J=10.2 Hz,J=8.8 Hz,1H), 9.15(s,1H), 9.26(s,1H)

EXAMPLE 20

Compound No.43 listed in Table 11 was synthesized in a similar manner toExample 4, proceeding from the corresponding compound No. 42 obtained inExample 19. The data are also shown in Table 11.

                                      TABLE 11                                    __________________________________________________________________________    Compound:                                                                      ##STR50##                                                                             Group                                                                Compound No.                                                                           R.sup.2                                                                         Y         Z Property                                                                              Melting point (°C.)                                                              .sup.1 H-NMR    Solvent              __________________________________________________________________________    43       H                                                                                ##STR51##                                                                               ##STR52##                                                                      Yellow solid                                                                          276  ∫ 280                                                                         [DMSO-d.sub.6 ] δ;                                                      1.8-2.05(m, 2H), 3.4-3.7(m, 3H),                                              .35(s, 1H), 5.05(s, 1H), 6.30(d,                                              J=7.8Hz, 1H), 7.86(d, J=14.2Hz,                                               1H), 8.90(s, 1H), 9.33(s,                                                                     MeCN Et.sub.3        __________________________________________________________________________                                                             N                

EXAMPLE 21

Compounds Nos. 44-53 listed in Tables 12-14 were synthesized in asimilar manner to Example 11, proceeding from the corresponding compoundNo.42 obtained in Example 19. The data are also shown in Tables 12-14.

                                      TABLE 12                                    __________________________________________________________________________    Compound:                                                                      ##STR53##                                                                    Compound                                                                            Group               Melting point                                       No.   R.sup.2                                                                         Y          Z Property                                                                           (°C.)                                                                         .sup.1 H-NMR      Solvent                    __________________________________________________________________________    44    H                                                                                ##STR54##                                                                                ##STR55##                                                                      Yellow needles                                                                     Colored from 235, 258.5-260                                                          [DMSO-d.sub.6 ] δ; 2.13(brs, 1H),                                       2.20-2.41(m, 1H), 6.34(d, J=7.3Hz, 1H),                                       7.91(d, J=14.2Hz, 1H), 8.48(brs, 3H),                                         8.94(s, 1H), 9.34(s, 1H)                                                                        MeCN Et.sub.3 N            45    H                                                                                ##STR56##                                                                                ##STR57##                                                                      Yellow needles                                                                     Colored from 210, 256-260                                                            [DMSO-d.sub.6 ] δ; 1.08(d,                                              J=6.8Hz, 3H), 2.60(brs, 1H), 6.30(d,                                          J=7.3Hz, 1H), 7.92(d, J=14.2Hz, 1H),                                          8.36(brs, 3H), 8.94(s, 1H), 9.34(s,                                                             MeCN Et.sub.3 N            __________________________________________________________________________

                                      TABLE 13                                    __________________________________________________________________________    Compound                                                                            Group                   Melting point                                   No.   R.sup.2                                                                         Y           Z  Property                                                                             (°C.)                                                                           .sup.1 H-NMR      Solvent              __________________________________________________________________________    46    H                                                                                ##STR58##                                                                                 ##STR59##                                                                       Orange solid                                                                         190  ∫ 197                                                                        [DMSO-d.sub.6 ] δ; 0.95(brs,                                            3H), 2.91(brs, 2H), 6.32(brs, 1H),                                            7.88(d, J=13.2Hz,                                                             1H), 7.80˜8.75(br, 3H),                                                 8.91(s, 1H), 9.36(s,                                                                            MeCN Et.sub.3 N      47    H                                                                                ##STR60##                                                                                 ##STR61##                                                                       Pale red solid                                                                       280  ∫ 285 Colored                                                                [DMSO-d.sub.6 ] δ; 1.24(brs,                                            3H), 1.71(brs, 1H), 2.08(brs, 1H),                                            2.40(brs, 1H), 6.32(brs, 1H),                                                 7.88(d, J=14.2Hz, 1H), 8.90(s,                                                1H), 9.32(s, 1H)  MeCN Et.sub.3 N      48    H                                                                                ##STR62##                                                                                 ##STR63##                                                                       Pale yellow solid                                                                    273  ∫ 280                                                                        [DMSO-d.sub.6 ] δ; 1.45(s,                                              3H), 2.08(brs, 1H), 2.22(brs, 1H),                                            6.36(brs, 1H), 7.93(d, J=14.2Hz,                                              1H), 8.55(brs, 3H), 8.94(s, 1H),                                              9.35(s, 1H)       MeCN Et.sub.3 N      49    H                                                                                ##STR64##                                                                                 ##STR65##                                                                       Pale yellow solid                                                                    Colored from 250, decomposed                                                           [DMSO-d.sub.6 ] δ; 3.34(s,                                              4H), 6.98(d, J=6.8Hz, 1H), 8.03(d,                                            J=13.2Hz, 1H), 9.02(s, 1H),                                                   9.35(s, 1H), 9.30˜9.82(br,                                              2H)               MeCN Et.sub.3        __________________________________________________________________________                                                             N                

                                      TABLE 14                                    __________________________________________________________________________    Compound                                                                            Group                  Melting point                                    No.   R.sup.2                                                                         Y          Z  Property                                                                             (°C.)                                                                           .sup.1 H-NMR       Solvent              __________________________________________________________________________    50    H                                                                                ##STR66##                                                                                ##STR67##                                                                       Pale yellow solid                                                                    Colored from 250, decomposed                                                           [DMSO-d.sub.6 ] δ; 2.80(s,                                              3H), 3.7(brs, 2H), 7.01(d, J=6.8Hz,                                           1H), 8.05(d, J=13.2Hz, 1H), 9.02(s,                                           1H), 9.35(s, 1H), 11.0˜11.4(br                                          , 1H)              MeCN Et.sub.3 N      51    H                                                                                ##STR68##                                                                                ##STR69##                                                                       Pale orange solid                                                                    230  ∫ 245 decomposed                                                             [DMSO-d.sub.6 ] δ; 3.85(brs,                                            2H), 4.1˜4.5(m, 2H), 6.52(d,                                            J=6.8Hz, 1H), 7.94(d, J=11.7Hz,                                               1H), 8.48(brs, 3H), 8.39(s, 1H),                                              9.33(s, 1H)        MeCN Et.sub.3 N      52    H                                                                                ##STR70##                                                                                ##STR71##                                                                       Pale orange solid                                                                    Colored from 210, 220-228                                                              [DMSO-d.sub.6 ] δ; 1.24(d,                                              J=6.4Hz)  1.39(d, J=5.8Hz)    3H),                                            3.5-4.1(m, 2H), 4.44(brs, 1H),                                                6.36(d, J=7.3Hz, 1H), 7.96(d,                                                 J=12.7HZ), 8.59(brs, 3H), 8.98(s,                                             1H), 9.32(s, 1H)   MeCN Et.sub.3 N      53    H                                                                                ##STR72##                                                                                ##STR73##                                                                       Yellow solid                                                                         Colored from 280, decomposed                                                           [DMSO-d.sub.6 ] δ; 1.9-2.15(m,                                           2H), 3.6-3.8(m, 3H), 4.44(s, 1H),                                            4.80(s, 1H), 6.54(d, J=7.3Hz, 1H),                                            7.97(d, J=13.7Hz, 1H), 8.95(s, 1H),                                           .15(brs, 1H), 9.32(s, 1H), 9.6(brs,                                           1H)                MeCN Et.sub.3        __________________________________________________________________________                                                             N                

EXAMPLE 22 Ethyl3-(1,2,3-thiadiazol-4-yl-amino)-2-(2,6-dichloro-5-fluoronicotinoyl)acrylate(Compound No.54)

A mixture of ethyl 2,6-dichloro-5-fluoronicotinoylacetate (5.6 g), ethylorthoformate (5.2 ml) and acetic anhydride (5.6 ml) was stirred at 130°C. for 3 hours. After the solvent was removed in vacuo, a solution of4-amino-1,2,3-thiadiazole hydrochloride (2.75 g) and triethylamine (2 g)in chloroform (20 ml) was added to the residue. The mixture was stirredat room temperature for 3 hours. The solvent was removed in vacuo. Theresidue was purified by chromatography on silicagel (chloroform/ethylacetate 20:1 as an eluent). The title compound No. 54 was obtained as apale yellow solid (7.8 g).

Melting point: 110.5°-113.5° C. ¹ H-NMR(CDCl₃) δ; 0.97 and 1.17 (t,J=7Hz,3H), 4.0-4.25 (m,2H), 7.44 and 7.54 (d,J=7 Hz, 1H), 8.14 and 8.19(s,1H), 9.0 and 9.22 (d,J=13 Hz,1H)

EXAMPLE 23 Ethyl7-chloro-6-fluoro-1-(1,2,3-thiadiazol-4-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate(Compound No.55)

To a solution of compound No.54 (7.8 g) obtained in Example 22 intetrahydrofuran (200 ml), 0.8 g of sodium hydride (60% in oil) was addedat room temperature. The solution was stirred for 0.5 hour at the sametemperature. After addition of aqueous 5% citric acid solution (40 ml),tetrahydrofuran was removed in vacuo. The precipitate was filtrated andwashed with water, ethanol and isopropyl ether. The title compound No.55 was obtained as a pale yellow solid (6.1 g).

Melting point: 188°-192° C. ¹ H-NMR(CDCl₃) δ; 1.42(t,J=7 Hz,3H),4.42(q,J=7 Hz,2H), 8.55(d,J=11.8 Hz,1H), 9.26(s,1H), 9.43(s,1H)

EXAMPLE 247-Chloro-6-fluoro-1-(1,2,3-thiadiazol-4-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (Compound No.56)

Compound No.55 (1 g) obtained in Example 23 was dissolved in a mixtureof acetic acid (10 ml) and 6N-HCl (4 ml). The solution was stirred at100° C. for 0.5 hour. After cooling, the precipitate was filtrated andwashed with water, ethanol and ether. The title compound No. 56 wasobtained as a pale yellow solid (0.9 g).

Melting point: 219-223° C. ¹ H-NMR(DMSO-d₆) δ; 8.79(d,J=7.3 Hz,1H),9.30(s,1H), 9.63(s,1H)

EXAMPLE 25 6-Fluoro-7-(pyrrolidin-1-yl)-1-(1,2,3-thiadiazole-4-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (Compound No.57)

A mixture of compound No.55 (216 mg) obtained in Example 23 andpyrrolidine (100 mg) in chloroform (5 ml) was stirred at roomtemperature for 1 hour. After evaporation of the solvent, acetic acid (1ml) and 6N-HCl(1 ml) were added to the residue, then stirred at 100° C.for 12 hours. After evaporation in vacuo, ethanol (5 ml) was added forfiltration, followed by washing with ethanol, chloroform and ether,successively. The title compound No. 57 was obtained as a colorlesssolid (140 mg).

Melting point: Colored and decomposed at 273° C. or more. ¹H-NMR(DMSO-d₆) δ; 1.87(brs,4H), 3.2-3.9(br,4H), 8.04(d,J=12.7 Hz,1H),9.09(s,1H), 9.65(s,1H)

EXAMPLE 26

Compounds Nos. 58-62 listed in Tables 15 and 16 were synthesized in asimilar manner to Example 25. The data are also shown in Tables 15-16.

                                      TABLE 15                                    __________________________________________________________________________    Compound:                                                                      ##STR74##                                                                    Compound                                                                            Group                 Melting point                                     No.   R.sup.2                                                                         Y          Z Property                                                                             (°C.)                                                                         .sup.1 H-NMR       Solvent                 __________________________________________________________________________    58    H                                                                                ##STR75## N Yellow solid                                                                         Colored from 212, decomposed                                                         [DMSO-d.sub.6 ] δ; 1.95˜2.3                                       (m, 2H), 3.85(brs, 2H), 8.15(d,                                               J=12.2Hz, 1H), 8.36(brs, 3H), 9.11(s,                                         1H), 9.70(s, 1H)                                                                                  ##STR76##              59    H                                                                                ##STR77## N Pale yellow solid                                                                    Colored from 246, 300 or more                                                        [DMSO-d.sub.6 ] δ; 1.06(d,                                              J=6.4Hz, 3H), 2.4-2.7(br, 1H),                                                3.1-4.2(m, 5H), 8.14(d, J=12.2Hz, 1H),                                        .35(brs, 3H), 9.11(s, 1H), 9.72(s,                                            1H),               "                       __________________________________________________________________________

                                      TABLE 16                                    __________________________________________________________________________    Compound                                                                            Group                 Melting point                                     No.   R.sup.2                                                                         Y          Z Property                                                                             (°C.)                                                                         .sup.1 H-NMR       Solvent                 __________________________________________________________________________    60    H                                                                                ##STR78## N Pale yellow solid                                                                    Colored from 288, decomposed                                                         [DMSO-d.sub.6 ] δ; 2.74(s, 3H),                                         2.9-3.2(m, 2H), 4.1-4.3(m, 2H),                                               8.32(d, J=13.2Hz, 1H), 9.17(s, 1H),                                           9.67(s, 1H), 10.4-10.6(br,                                                                        ##STR79##              61    H                                                                                ##STR80## N Pale yellow solid                                                                    Colored from 239, decomposed                                                         [DMSO-d.sub.6 ] δ; 3.13(s, 4H),                                         3.80(s, 4H), 8.26(d, J=12.7Hz, 1H),                                           9.14(s, 1H), 9.50(brs, 2H), 9.67(s,                                           1H)                "                       62    H                                                                                ##STR81## N Colorless solid                                                                      Colored from 240, decomposed                                                         [DMSO-d.sub.6 ] δ; 3.51(brs,                                            3H), 3.73(brs, 2H), 8.15(d, J=10.2Hz,                                         1H), 8.42(brs, 2H), 8.56(brs, 1H),                                            9.1(s, 1H), 9.75(s, 1H)                                                                          "                       __________________________________________________________________________

EXAMPLE 27 Ethyl2-(2,4,5-trifluorobenzoyl)-3-(1,2,3-thiadiazol-4-ylamino)acrylate(Compound No.63)

A mixture of ethyl 2,4,5-trifluorobenzoylacetate (4.92 g), ethylorthoformate (5.2 ml) and acetic anhydride (5.6 ml) was stirred at 130°C. for 8 hours. After the solvent was removed in vacuo, a solution of4-amino-1, 2,3-thiadiazole hydrochloride (2.75 g) and triethylamine(2 g)in chloroform(20 ml) was added to the residue. The mixture was stirredat room temperature for 1 day. The solvent was removed in vacuo. Theresidue was purified by chromatography on silicagel (chloroform/ethylacetate 30:1 as an eluent). The title compound No. 63 was obtained as apale yellow solid (7.1 g).

Melting point: 104°-106° C. ¹ H-NMR(CDCl₃) δ; 1.04 and 1.18(t,J=7Hz,3H), 4.05-4.2(m,2H), 6.85-7.0(m,1H), 7.2-7.6(m,1H), 8.02 and8.09(s,1H) 8.73 and 9.06(d,J=13 Hz,1H),

EXAMPLE 28 Ethyl6,7-difluoro-1-(1,2,3-thiadiazol-4-yl)1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.64)

To a solution of compound No.63 (7.1 g) obtained in Example 27 intetrahydrofuran (200 ml), 0.8 g of sodium hydride (60% in oil) wasadded. Then the solution was stirred for 1 hour at room temperature.After addition of 5% aqueous citric acid solution (30 ml),tetrahydrofuran was removed in vacuo. The aqueous solution was extractedwith chloroform (300 ml). The organic phase was dried (Na₂ SO₄) andevaporated. The residue was purified by chromatography on silicagel(chloroform/ethyl acetate 5:1 as an eluent). The title compound No. 64was obtained as a yellow solid (3.3 g).

Melting point: 198°-203° C. ¹ H-NMR(CDCl₃) δ; 1.34(t,J=7 Hz,3H),4.29(q,J=7 Hz,2H), 6.81(dd,J=5.9 Hz,J=10.7 Hz,1H), 8.08(dd,J=8.3Hz,J=10.2 Hz,1H), 8.46(s,1H), 9.43(s,1H)

EXAMPLE 296,7-Difluoro-1-(1,2,3-thiadiazol-4-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.65)

Compound No.64 (0.18 g) obtained in Example 28 was dissolved in aceticacid (1 ml) and 6N-HCl (1 ml). The solution was stirred at 100° C. for 1hour. Water (30 ml) was added thereto, and the solid matter wascollected by filtration, followed by washing with water, ethanol andether successively. The title compound No. 65 was obtained as a yellowsolid (115 mg).

Melting point: 239°-244° C. ¹ H-NMR(DMSO-d₆) δ;7.54(dd,J=11.7 Hz,J=6.8Hz,1H), 8.36(dd,J=9.8 Hz,J=8.8 Hz,1H), 9.10(s,1H), 9.77(s,1H)

EXAMPLE 30 Ethyl7-chloro-6-fluoro-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate(Compound No.66)

A mixture of ethyl 2,6-dichloro-5-fluoronicotinoylacetate (4.2 g), ethylorthoformate (3.9 ml) and acetic anhydride (4.3 ml) was stirred at 135°C. for 2 hours. After the solvent was removed in vacuo, the residue wasadded with chloroform (20 ml) and ethanol (10 ml).3-Methyl-5-amino-1,2,4-thiadiazole (1.73 g) was added thereto at roomtemperature and allowed to react at the same temperature for 1 hour. Thesolvent was removed. The residue was purified by chromatography onsilicagel (chloroform/methanol 40:1 as an eluent). An yellow oil (5.8 g)was obtained. To a solution of this oily compound (400 g) inN,N-dimethylformamide (5 ml), 40 mg of sodium hydride (60% in oil) wasadded. Then the solution was stirred for 0.5 hour at 100° C. The solventwas removed. The residue was added with chloroform and water forseparating an organic phase. The organic phase was washed dried (Na₂SO₄) and evaporated for collecting the precipitated solid. The titlecompound No.66 was obtained as a colorless solid (0.18 g).

Melting point: 235°-237° C. ¹ H-NMR(CDCl₃) δ; 1.46(t,J=7 Hz,3H),2.69(s,3H), 4.47(q,J=7 Hz,2H), 8.54(d,J=7 Hz,1H), 9.96(s,1H)

EXAMPLE 317-Chloro-6-fluoro-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (Compound No.67)

Compound No.66 (1g) obtained in Example 30 was dissolved in acetic acid(40 ml) and c-HCl (10 ml). The solution was stirred at 100° C. for 0.5hour. After evaporating the solvent, the residue was added with waterfollowed by filtration, washing with water, ethanol, ether and n-hexanesuccessively. The title compound No. 67 was obtained as a colorlesssolid (0.84 g).

Melting point: 260°-262° C. ¹ H-NMR(DMSO-d₆) δ; 2.63(s,3H), 8.78(d,J=8Hz,1H), 9.75(s,1H)

EXAMPLE 326-Fluoro-7-(pyrrolidin-1-yl)-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (Compound No.68)

Compound No.66 (100 mg) obtained in Example 30 was dissolved inchloroform (4 ml), to which pyrrolidine (44 mg) and triethylamine (30mg) were added for allowing to react at room temperature for 10 minutes.After evaporation of the solvent, acetic acid (2 ml) and c-HCl (1 ml)were added, then stirred at 100° C. for 1.5 hours. The precipitatedsolid was collected by filtration and washed with ethanol, ether andn-hexane, successively. The title compound No. 68 was obtained as a paleyellow solid (40 mg).

Melting point: 300° C. or more ¹ H-NMR(CDCl-₁₃) δ; 2.15(brs,4H),2.66(s,3H), 3.98(s,4H), 8.01(d,J=13 Hz,1H), 10.02(s,1H)

EXAMPLE 33

Compounds Nos. 69-72 listed in Tables 17-18 were synthesized in asimilar manner to Example 32. The data are also shown in Tables 17-18.

                                      TABLE 17                                    __________________________________________________________________________    Compound:                                                                      ##STR82##                                                                    Compound                                                                            Group                   Melting point                                   No.   R.sup.2                                                                          Y          Z  Property                                                                             (°C.)                                                                          .sup.1 H-NMR       Solvent              __________________________________________________________________________    69    H                                                                                 ##STR83## N  Pale yellow solid                                                                    Colored from 220, decomposed                                                          [DMSO-d.sub.6 ] δ; 2.26(brs,                                            1H), 2.40(brs, 1H), 2.64(s, 3H),                                              4.07-4.25(br, 4H), 8.19(d, J=13Hz,                                            1H), 8.0-8.7(br, 3H), 9.73(s,                                                                     ##STR84##           70    H                                                                                 ##STR85## N  Colorless solid                                                                      Colored from 250, decomposed                                                          [DMSO-d.sub.6 ] δ; 2.65(s,                                              1H), 2.84(s, 3H), 8.35(d, J=13Hz,                                             1H), 9.75(s, 1H), 11.0-11.5(br,                                                                  "H)                  __________________________________________________________________________

                                      TABLE 18                                    __________________________________________________________________________    Compound                                                                            Group                 Melting point                                     No.   R.sup.2                                                                         Y          Z Property                                                                             (°C.)                                                                         .sup.1 H-NMR    Solvent                    __________________________________________________________________________    71    H                                                                                ##STR86## N Yellow solid                                                                         Colored from 260, decomposed                                                         [DMSO-d.sub.6 ]δ; 2.65(s, 3H),                                          4.09(brs, 4H), 8.33(d, J=13Hz, 1H),                                           9.75(s, 1H)                                                                                    ##STR87##                 72    H                                                                                ##STR88## N Pale yellow solid                                                                    Colored from 190, decomposed                                                         [DMSO-d.sub.6 ] δ; 1.16(d,                                              J=7Hz, 3H), 2.64(s, 3H), 2.80(brs,                                            1H), 3.74-4.04(br, 2H), 8.18(d,                                               J=13Hz, 1H), 9.72(s,                                                                           ##STR89##                 __________________________________________________________________________

EXAMPLE 34 Ethyl6,7-difluoro-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.73)

A mixture of ethyl 2,4,5-trifluorobenzoylacetate (3.7 g), ethylorthoformate (3.9 ml) and acetic anhydride (4.3 ml) was stirred at 135°C. for 3 hours. After the solvent was removed in vacuo, the residue wasadded with chloroform (20 ml) and ethanol (10 ml).3-Methyl-5-amino-1,2,4-thiadiazole (1.73 g) was added thereto forallowing to react for 15 hours at the same temperature. The solvent wasremoved. The residue was purified by chromatography onsilicagel(chloroform/ethyl acetate 1:1 as an eluent). An yellow oil (4.9g) was obtained. To a solution of this oily compound (4.5 g) inN,N-dimethylformamide (60 ml), 490 mg of sodium hydride (60% in oil) wasadded . Then the solution was stirred for 5 minutes at 100° C. Thesolvent was removed. The residue was added with chloroform and water,for extracting an organic layer, followed by evaporation. Theprecipitated solid was collected and washed with ethanol, ether andn-hexane, successively. The title compound No. 73 was obtained as a palebrown solid (2.4 g).

Melting point: 157°-159° C. ¹ H-NMR(CDCl₃) δ; 1.42(t,J=7 Hz,3H),2.78(s,3H), 4.43(q,J=7 Hz,2H), 8.17-8.32(m,2H), 8.77(s,1H)

EXAMPLE 35 6,7-Difluoro-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound No.74)

Compound No.73 (1.2 g) obtained in Example 34 was dissolved in a mixtureof tetrahydrofuran (40 ml) and HCl (10 ml). The solution was reacted at100° C. for 40 minutes. After evaporation, to the residue was addedwater, and the solid matter was collected by filtration, followed bywashing with water, ethanol, ether and n-hexane, successively. The titlecompound No. 74 was obtained as a pale brown solid (0.9 g).

Melting point: 235°-238° C. ¹ H-NMR(DMSO-d₆) δ; 2.69(s,3H), 8.06(dd,J=7Hz,J=12 Hz,1H), 8.32(dd,J=9 Hz,J=10 Hz,1H), 9.04(s,1H)

EXAMPLE 366-Fluoro-7-(3-aminoazetidin-1-yl)-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacidhydrochloride (Compound No. 75)

Compound No.74 (90 mg) obtained in Example 35 was added to acetonitrile(4 ml), to which triethylamine (0.12 g) and 3-aminoazetidinedihydrochloride (54 mg) were further added for allowing to react at 80°C. for 60 minutes. After cooling, the precipitate was filtrated andwashed with ethanol, ether and n-hexane, successively to obtain a paleyellow solid (43 mg). A 20 mg portion was taken and added to a mixtureof tetrahydrofuran (2 ml) and 6N-HCl (0.5 ml), and stirred for 5minutes. The precipitate was collected by filtration and washed withwater, ethanol, ether and n-hexane successively. The title compound No.75 was obtained as a pale yellow solid (15 mg).

Melting point: Colored and decomposed at 270° C. or more. ¹H-NMR(DMSO-d₆) δ; 2.69(s,3H), 4.16(br,3H), 4.42(brs,2H), 6.67(d,J=8Hz,1H), 7.92(d,J=13 Hz,1H), 8.5-8.7(brs,3H), 8.89(s,1H)

EXAMPLE 37

Compound No.76 listed in Table 19 was prepared in a similar manner toExample 36. The data are also shown in Table 19.

                                      TABLE 19                                    __________________________________________________________________________    Compound:                                                                      ##STR90##                                                                    Compound                                                                            Group                   Melting point                                   No.   R.sup.2                                                                          Y          Z  Property                                                                             (°C.)                                                                          .sup.1 H-NMR       Solvent              __________________________________________________________________________    76    H                                                                                 ##STR91##                                                                                ##STR92##                                                                       Pale yellow solid                                                                    Colored from 159, decomposed                                                          [DMSO-d.sub.6 ] δ; 1.09(brs,                                            3H), 2.51-2.71(m, 1H), 2.71(s, 3H),                                           .08-3.90(m, 5H), 6.72(d, J=7Hz,                                               1H), 7.92(d, J=14Hz, 1H),                                                     8.2-8.6(br, 3H) 8.92(s,                                                                           ##STR93##           __________________________________________________________________________

EXAMPLE 38 Ethyl3-(4-methyl-1,2,5-oxadiazol-3-ylamino)-2-(2,6-dichloro-5-fluoronicotinoyl)acrylate(Compound No.77)

A mixture of ethyl 2,6-dichloro-5-fluoronicotinoylacetate (1.4 g), ethylorthoformate (1.3 ml) and acetic anhydride (1.4 ml) was stirred at 130°C. for 17 hours. After the solvent was removed in vacuo, a solution of3-amino-4-methyl-1,2,5-oxadiazole (545 mg) in chloroform (5 ml) wasadded to the residue. The mixture was stirred at room temperature for 24hours. The solvent was removed and the residue was purified bychromatography on silicagel(chloroform as an eluent). The title compoundNo. 77 was obtained as a colorless solid (770 mg).

Melting point: 139-141.5° C. ¹ H-NMR(CDCl₃) δ; 0.97 and 1.18(t,J=7Hz,3H), 2.47 and 2.51(s,3H), 4.05-4.3(m,2H), 7.3 and 7.43(d,J=6.8Hz,1H), 8.72 and 8.82(d,J=12.4 Hz,1H)

EXAMPLE 39

Ethyl7-chloro-6-fluoro-1-(4-methyl-1,2,5-oxadiazol-3-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate(Compound No.78)

To a solution of compound No.77 (0.7 g) obtained in Example 38 intetrahydrofuran (30 ml), 0.074 g of sodium hydride (60% in oil) wasadded with ice cooling. Then the solution was stirred for 4 hours atroom temperature. The solvent was removed. After addition of aqueous 5%citric acid solution (20 ml), extraction was carried out with chloroform(50 ml). The chloroform was evaporated and the residue was purified bychromatography on silicagel (chloroform/ethyl acetate 1:1 as an eluent).The title compound No. 78 was obtained as a pale yellow solid (0.41 g).

Melting point: 211°-216° C. ¹ H-NMR(CDCl₃) δ; 1.40(t,J=7 Hz,3H),2.41(s,3H), 4.41(q,J=7 Hz,2H), 8.49(d,J=7.8 Hz,1H), 8.66(s,1H)

EXAMPLE 407-Chloro-6-fluoro-1-(4-methyl-1,2,5-oxadiazol-3-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (Compound No.79)

Compound No. 78 (30 mg) obtained in Example 39 was dissolved in aceticacid (2 ml ) and 6N-HCl (0.5 ml). The solution was stirred at 100° C.for 0.5 hour. After cooling and addition of water (10 ml), theprecipitate was filtrated and washed with ethanol and ether. The titlecompound No. 79 was obtained as a colorless solid (5 mg).

Melting point: 242°-247° C. ¹ H-NMR(DMSO-d₆) δ; 2.33(s,3H), 8.77(d,J=8HZ,1H), 9.09(s,1H)

EXAMPLE 416-Fluoro-7-(4-methylpiperazin-1-yl)-1-(4-methyl-1,2,5-oxadiazol-3-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid hydrochloride (Compound No.80)

A mixture of compound No.78 (0.15 g)obtained in Example 40,triethylamine (40 mg) and N-methylpiperazine (70 mg) in acetonitrile (5ml) was stirred at 50° C. for 20 minutes. After the solvent was removed,1 ml of 6N-HCl and 1 ml of acetic acid were added, then stirred at 100°C. for 1 hour. After the solvent was removed in vacuo, ethanol(5 ml) wasadded to the residue. The precipitate was collected by filtration andwashed with ethanol and ether. The title compound No. 80 was obtained asa colorless solid (0.16 g).

Melting point: 254°-258° C. ¹ H-NMR(DMSO-d₆) δ; 2.31(s,3H), 2.74(s,3H),3.08(brs,2H), 3.3-3.6(m,4H), 4.18(brs,2H), 8.29(d,J=13.2 Hz,1H),9.00(s,1H)

EXAMPLE 42

Compounds Nos. 81-89 listed in Tables 20-22 were synthesized in asimilar manner to Example 41. The data are also shown in Tables 20-22.

                                      TABLE 20                                    __________________________________________________________________________    Compound:                                                                      ##STR94##                                                                    Compound                                                                            Group                 Melting point                                     No.   R.sup.2                                                                         Y          Z Property                                                                             (°C.)                                                                         .sup.1 H-NMR      Solvent                  __________________________________________________________________________    81    H                                                                                ##STR95## N Pale yellow solid                                                                    Colored from 245, decomposed from                                                    [DMSO-d.sub.6 ] δ; 2.0-2.4(m,                                           2H), 2.34(s, 3H), 3.2-4.1(m, 5H),                                             8.13(d, J=12Hz, 1H), 8.37(brs, 3H),                                           8.92(s, 1H)                                                                                      ##STR96##               82    H                                                                                ##STR97## N Pale yellow solid                                                                    Colored from 255, decomposed from                                                    [DMSO-d.sub.6 ] δ; 1.08(d,                                              J=6.8Hz, 3H), 2.34(s, 3H), 2.4-2.7(br,                                        1H), 3.4-4.2(m, 3H), 8.14(d, J=12.2Hz,                                        1H), 8.37(brs, 3H), 8.92(s,                                                                     "H)                      __________________________________________________________________________

                                      TABLE 21                                    __________________________________________________________________________    Compound                                                                            Group                 Melting point                                     No.   R.sup.2                                                                         Y          Z Property                                                                             (°C.)                                                                         .sup.1 H-NMR       Solvent                 __________________________________________________________________________    83    H                                                                                ##STR98## N Colorless solid                                                                      300 or more                                                                          [DMSO-d.sub.6 ] δ; 1.44(s, 3H),                                         1.9-2.4(m, 2H), 2.34(s,                                                       3H), 3.4-4.3(m, 4H), 8.13(d, J=14.7Hz,                                        1H), 8.56(brs, 3H), 8.92(s,                                                                       ##STR99##              84    H                                                                                ##STR100##                                                                              N Colorless solid                                                                      224  ∫ 226.5                                                                    [DMSO-d.sub.6 ] δ; 1.9(brs, 2H),                                        2.31(s, 3H), 3.9(brs, 1H), 4.3(brs,                                           1H), 5.05(brs, 1H), 8.06(d, J=12.2Hz,                                         1H), 8.91(s, 1H)   "                       85    H                                                                                ##STR101##                                                                              N Pale yellow solid                                                                    Decomposed from 276                                                                  [DMSO-d.sub.6 ] δ; 2.32(s, 3H),                                         3.18(s, 4H), 3.81(s, 4H), 8.24(d,                                             J=13.2Hz, 1H), 8.98(s, 1H), 9.59(brs,                                         1H), 9.79(brs, 1H) "                       86    H                                                                                ##STR102##                                                                              N Colorless solid                                                                      Decomposed from 292                                                                  [DMSO-d.sub.6 ] δ; 1.9-2.2(m,                                           2H), 2.32(s, 3H), 4.45(s, 1H), 8.21(d,                                        J=13Hz, 1H), 8.96(s, 1H), 8.95(brs,                                           2H)                "                       __________________________________________________________________________

                                      TABLE 22                                    __________________________________________________________________________    Compound                                                                            Group                Melting point                                      No.   R.sup.2                                                                         Y          Z  Property                                                                           (°C.)                                                                         .sup.1 H-NMR        Solvent                 __________________________________________________________________________    87    H                                                                                ##STR103##                                                                              N  Colorless solid                                                                    Decomposed from 297                                                                  [DMSO-d.sub.6 ] δ; 2.1-2.4(m, 2H)                                       2.33(s, 3H), 2.83(s, 3H), 3.0-3.2(m,                                          (1H) 3.5-3.7(m, 1H), 4.38(s, 1H),                                             8.22(d J=11.7Hz, 1H), 8.96(s, 1H),                                            10.4(brs, 1H)                                                                                      ##STR104##             88    H                                                                                ##STR105##                                                                              N  Colorless solid                                                                    Decomposed from 241                                                                  [DMSO-d.sub.6 ] δ; 2.31(s, 3H),                                         3.57(brs, 2H), 3.72(brs, 2H), 8.14(d,                                         J=10.2Hz, 1H), 8.44(brs, 2H), 8.65(brs,                                       1H), 8.93(s, 1H)    "                       89    H                                                                                ##STR106##                                                                              N  Colorless solid                                                                    218  ∫ 225                                                                      [DMSO-d.sub.6 ] δ; 2.33(s, 3H),                                         2.85(brs, 2H), 3.18(brs, 2H), 8.12(brs,                                       3H), 8.47(d, J=8.8Hz, 1H), 9.18(s,                                                                "H)                     __________________________________________________________________________

EXAMPLE 43 Ethyl3-(4-methyl-1,2,5-oxadiazol-3-ylamino)-2-(2,4,5-trifluorobenzoyl)acrylate(Compound No.90)

A mixture of ethyl 2,4,5-trifluorobenzoylacetate (2.46 g), ethylorthoformate (2.6 ml) and acetic anhydride (2.8 ml) was stirred at 130°C. for 6 hours. After the solvent was removed in vacuo, a solution of3-amino-4-methyl-1, 2,5-oxadiazole (1.04 g) in chloroform (10 ml) wasadded to the residue. The mixture was stirred at room temperature for 24hours, then the solvent was removed. The residue was purified bychromatography on silicagel (chloroform as an eluent). The titlecompound No. 90 was obtained as a colorless solid (1.95 g).

Melting point: 104°-107° C. ¹ H-NMR(CDCl₃) δ; 1.05 and 1.20(t,J=7Hz,3H), 2.45 and 2.48(s,3H), 4.1-4.3(m,2H), 6.85-7.0(m,1H), 7.3-7.41 and7.48-7.6(m,1H), 8.39 and 8.69(q,J=12 Hz,1H)

EXAMPLE 44 Ethyl6,7-difluoro-1-(4-methyl-1,2,5-oxadiazol-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.91)

To a solution of compound No.90 (1.9 g) obtained in Example 43 intetrahydrofuran (50 ml), 216 mg of sodium hydride (60% in oil) wasadded. Then the solution was stirred for 6 hour at the room temperature.The solvent was removed and the residue was added with aqueous 5% citricacid solution (30 ml), followed by extraction with chloroform (50 ml),and evaporation. The residue was purified by chromatography on silicagel(chloroform/ethyl acetate 1:1 as an eluent). The title compound No. 91was obtained as a colorless solid (1.18 g).

Melting point: 178°-180.5° C. ¹ H-NMR(CDCl₃) δ; 1.40(t,J=7 Hz,3H),2.41(s,3H), 4.39(q,J=7 Hz,2H), 6.81(dd,J=10.2 Hz,J=5.8 Hz,1H),8.30(dd,J=9.8 Hz,J=8.8 Hz,1H), 8.39(s,1H)

EXAMPLE 456,7-Difluoro-1-(4-methyl-1,2,5-oxadiazol-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.92)

Compound No.91 (0.1 g) obtained in Example 44 was dissolved in aceticacid (3 ml) and 6N-HCl (1 ml). The solution was stirred at 100° C. for 2hours. After cooling, the precipitate was filtrated and washed withwater, ethanol and ether. The title compound was obtained as colorlesssolid(60 mg).

Melting point: 238-241° C. ¹ -NMR(DMSO-d₆) δ; 2.33(s,3H), 7.78(dd,J=11.2Hz,J=6.3 Hz,1H), 8.34(dd,J=10.3 Hz,J=8.3 Hz,1H), 9.16(s,1H)

EXAMPLE 46

Compound Nos. 93-95 listed in Tables 23 and 24 were synthesized in asimilar manner to Example 11, proceeding from the corresponding compoundNo.92 obtained in Example 45. The data are also shown in Tables 23-24.

                                      TABLE 23                                    __________________________________________________________________________    Compound:                                                                      ##STR107##                                                                   Compound                                                                            Group                 Melting point                                     No.   R.sup.2                                                                         Y          Z Property                                                                             (°C.)                                                                         .sup.1 H-NMR       Solvent                 __________________________________________________________________________    93    H                                                                                ##STR108##                                                                               ##STR109##                                                                     Pale yellow solid                                                                    Decomposed from 292                                                                  [DMSO-d.sub.6 ] δ; 2.0-2.3(m,                                           2H), 2.36(s, 3H), 3.74-4.0(m, 2H),                                            598(d, J=6.8Hz, 1H), 7.93(d, J=14Hz,                                          1H), 8.37(brs, 3H), 8.97(s,                                                                       ##STR110##             94    H                                                                                ##STR111##                                                                               ##STR112##                                                                     Pale yellow solid                                                                    274  ∫ 279                                                                      [DMSO-d.sub.6 ] δ; 1.08(d,                                              J=6.8Hz, 3H), 2.36(s, 3H), 2.5-2.7(m,                                         1H), 3.5-4.0(m, 4H), 5.95(d, J=7.3Hz,                                         1H), 7.93(d, J=14Hz, 1H), 8.1-8.8(br,                                         3H) 8.97(s, 1H)    "                       __________________________________________________________________________

                                      TABLE 24                                    __________________________________________________________________________    Compound                                                                            Group            Melting point                                          No.   R.sup.2                                                                         Y       Z Property                                                                           (°C.)                                                                         .sup.1 H-NMR     Solvent                        __________________________________________________________________________    95    H                                                                                ##STR113##                                                                            ##STR114##                                                                     Colorless solid                                                                    278  ∫ 285                                                                      [DMSO-d.sub.6 ] δ; 2.34(s, 3H),                                         3.23(s, 4H), 3.44(s, 4H), 6.66(d, J=6.8Hz,                                    1H), 8.04(d, J=12.7Hz, 1H), 9.06(s, 1H),                                      9.52(brs, 2H)                                                                                   ##STR115##                    __________________________________________________________________________

EXAMPLE 47 Ethyl3-(1,2,4-triazol-4-ylamino)-2-(2,4,5-trifluorobenzoyl)acrylate (CompoundNo.96)

A mixture of ethyl 2,4,5-trifluorobenzoylacetate (4.29 g), ethylorthoformate (5.2 ml) and acetic anhydride (5.6 ml) was stirred at 130°C. for 6 hours. After the solvent was removed in vacuo, a solution of4-amino-1,2,4-triazole (1.77 g) and ethanol (5 ml) in chloroform (30 ml)was added to the residue. The mixture was stirred at room temperaturefor 6 hours. The solvent was removed, the residue was added with 100 mlof hexane, then the solution was stirred for 1 hour. The precipitate wasfiltrated. The title compound No. 96 was obtained as a colorless solid(6.2 g).

Melting point: 239°-240° C. ¹ H-NMR(CDCl₃) δ; 1.0-1.2(m,3H), 4.14(q,J=7Hz,2H), 6.85-7.1(m,1H), 7.3-7.6(m,1H), 8.18(brs,1H), 8.46(s,2H)

EXAMPLE 48 Ethyl6,7-difluoro-1-(1,2,4-triazol-4-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.97)

A solution of compound No.96 (6.2 g) obtained in Example 47 andanhydrous potassium carbonate (2.5 g) in N,N-dimethylformamide (20 ml)was stirred for 4 hours at 90° C. The solvent was removed in vacuo.After addition of water, the precipitate was filtrated and washed withwater, ethanol and ether successively. The title compound No. 97 wasobtained as a pale green solid (3.7 g).

Melting point: 269°-274° C. ¹ H-NMR(DMSO-d₆) δ; 1.26((t,J=7 Hz,3H),4.22(q,J=7 Hz,2H), 6.9(dd,J=11 Hz,J=6.4 Hz,1H), 8.14(dd,J=10.2 Hz,J=8.3Hz,1H), 9.01(s,1H),9.20(s,2H)

EXAMPLE 496,7-Difluoro-1-(1,2,4-triazol-4-y1)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.98)

Compound No.97 (3.0 g) obtained in Example 48 was dissolved in a mixtureof tetrahydrofuran (120 ml) and 6N-HCl (30 ml). The solution was stirredat reflux temperature for 20 minutes. After cooling, 200 ml of water wasadded. The precipitate was filtrated and washed with ethanol, ether andhexane. The title compound No. 98 was obtained as a colorless solid (1.6g).

Melting point: 270° C. decomposed ¹ H-NMR(DMSO-d₆) δ; 7.09(dd,J=11Hz,J=6 Hz,1H), 8.36(dd,J=10 Hz,J=8 Hz,1H), 9.18(s,2H), 9.34(s,1H)

EXAMPLE 506-Fluoro-7-(4-methylpiperazin-1-yl)-1-(1,2,4-triazol-4-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.99)

A mixture of compound No.98 (50 mg) obtained in Example 49 andN-methylpiperazine (40 mg) in acetonitrile (3 ml) was stirred at 80° C.for 60 minutes. After the solvent was removed, ethanol was added to theresidue. The precipitate was filtrated and washed with ethanol and ethersuccessively. The title compound No. 99 was obtained as a yellow solid(43 mg).

Melting point: 270° C. decomposed ¹ H-NMR(DMSO-d₆) δ; 2.20(s,3H),2.43(brs,4H), 3.13(brs,4H), 5.83(d,J=7 Hz,1H), 8.00(d,J=14 Hz,1H),9.21(s,2H), 9.26(s,1H)

EXAMPLE 51

Compound Nos. 100-103 listed in Tables 25 and 26 were synthesized in asimilar manner to Example 50. The data are also shown in Tables 25 and26.

                                      TABLE 25                                    __________________________________________________________________________    Compound:                                                                      ##STR116##                                                                   Compound                                                                            Group                 Melting point                                     No.   R.sup.2                                                                         Y          Z Property                                                                             (°C.)                                                                         .sup.1 H-NMR  Solvent                      __________________________________________________________________________    100   H                                                                                ##STR117##                                                                               ##STR118##                                                                     Pale yellow solid                                                                    300 or more                                                                          [DMSO-d.sub.6 ] δ; 2.81(brs,                                            4H), 3.05(brs, 4H), 5.79(d, J=7Hz,                                            1H), 7.98(d, J=14Hz, 1H), 9.22(s, 2H),                                        9.25(s, 1H)   CH.sub.3 CN Et.sub.3 N       101   H                                                                                ##STR119##                                                                               ##STR120##                                                                     Colorless solid                                                                      300 or more                                                                          [DMSO-d.sub.6 ] δ; 4.21(brs, 2H)                                        .11(d, J=7Hz, 1H), 7.87(d, J=13Hz,                                            1H), 9.15(s, 2H), 9.20(s,                                                                   CH.sub.3 CN Et.sub.3         __________________________________________________________________________                                                     N                        

                                      TABLE 26                                    __________________________________________________________________________    Compound                                                                            Group                   Melting point                                   No.   R.sup.2                                                                          Y          Z  Property                                                                             (°C.)                                                                          .sup.1 H-NMR       Solvetn              __________________________________________________________________________    102   H                                                                                 ##STR121##                                                                               ##STR122##                                                                      Brown solid                                                                          300 or more                                                                           [DMSO-d.sub.6 ] δ; 1.59-2.01(m                                          , 2H), 2.76-3.19(m, 5H), 5.27(d,                                              J=7Hz, 1H), 7.86(d, J=14Hz, 1H),                                              9.09(s, 1H), 9.23(s,                                                                             CH.sub.3 CN          103   H                                                                                 ##STR123##                                                                               ##STR124##                                                                      Pale yellow solid                                                                    300 or more                                                                           [DMSO-d.sub.6 ] δ; 0.96(d,                                              J=7Hz, 3H), 2.07-2.22(m, 1H),                                                 3.17-3.52(m, 5H), 5.25(d, J=7Hz,                                              1H), 7.85(d, J=14Hz, 1H), 9.13(s,                                             1H), 9.22(s, 2H)   CH.sub.3 CN                                                                   Et.sub.3             __________________________________________________________________________                                                             N                

EXAMPLE 52 Ethyl3-(1,2,4-triazol-4-ylamino)-2-(2,6-dichloro-5-fluoronicotinoyl)acrylate(Compound No.104)

A mixture of ethyl 2,6-dichloro-5-fluoronicotinoylacetate (4.2g), ethylorthoformate (3.9 ml) and acetic anhydride (4.3 ml) was stirred at 130°C. for 2 hours. After the solvent was removed in vacuo, a solution of4-amino-1,2,4-triazole (1.26 g) in chloroform (20 ml) was added to theresidue. The mixture was stirred at room temperature for 4 hours. Thesolvent was removed and the residue was added with isopropylether. Theprecipitate was filtrated. The title compound No. 104 was obtained as ayellow solid (5.5 g).

Melting point: 89°-95° C. ¹ H-NMR(CDCl₃) δ; 1.27(t,J=7 Hz,3H),4.24(q,J=7 Hz,2H), 8.6(d,J=7.6 Hz,1H), 9.04(s,2H), 9.22(s,1H)

EXAMPLE 53 Ethyl7-chloro-6-fluoro-1-(1,2,4-triazol-4-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate(Compound No.105)

A solution of compound No.104 (0.95 g) obtained in Example 52 and sodiumhydrogencarbonate (0.21 g) in N,N-dimethylformamide (5 ml) was stirredfor 1 hour at 100° C. The solution was removed in vacuo. After additionof water to the residue, the precipitate was filtrated and washed withwater, ethanol and ether successively. The title compound No. 105 wasobtained as a pale yellow solid (0.52 g).

Melting point: 257° C. decomposed ¹ H-NMR(CDCl₃) δ; 1.08(t,J=7 Hz,3H),4.11(q,J=7 Hz,2H), 7.47(d,J=6.8 Hz,1H), 8.27(s,1H), 8.47(s,2H)

EXAMPLE 547-Chloro-6-fluoro-1-(1,2,4-triazol-4-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (Compound No.106)

Compound No.105 (1.0 g) obtained in Example 53 was dissolved in aceticacid (40 ml) and 6N-HCl (10 ml). The solution was stirred at 100° C. for0.5 hour. After cooling, water (100 ml) is added thereto, and theprecipitate was filtrated and washed with ethanol and ethersuccessively. The title compound No. 106 was obtained as a pale yellowsolid (0.48 g).

Melting point: 230° C. decomposed ¹ H-NMR(DMSO-d₆) δ; 8.77(d,J=8 Hz,1H),9.03(s,2H), 9.44(s,1H)

EXAMPLE 556-Fluoro-7-(4-methylpiperazin-1-yl)-1-(1,2,4-triazol-4-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (Compound No.107)

A mixture of compound No.106 (30 mg) obtained in Example 54 andN-methylpiperazine (20 mg) in acetonitrile (2 ml) was stirred at 80° C.for 60 minutes. After the solvent was removed, ethanol (5 ml) was addedto the residue. The precipitate was filtrated and washed with ethanoland ether successively. The title compound No. 107 was obtained as acolorless solid (7 mg).

Melting point: 271° C. decomposed ¹ H-NMR(DMSO-d₆) δ; 2.32(s,3H),3.06(brs,4H), 3.59(brs,4H), 8.21(d,J=13 Hz,1H), 9.01(s,2H), 9.33(s,1H)

EXAMPLE 56

Compound Nos. 108-110 listed in Table 27 were prepared in a similarmanner to Example 55. The data are also shown in Table 27.

                                      TABLE 27                                    __________________________________________________________________________    Compound:                                                                      ##STR125##                                                                   Compound                                                                            Group                Melting point                                      No.   R.sup.2                                                                         Y          Z Property                                                                            (°C.)                                                                         .sup.1 H-NMR     Solvent                    __________________________________________________________________________    108   H                                                                                ##STR126##                                                                              N Colorless solid                                                                     Decomposed from 220                                                                  [DMSO-d.sub.6 ] δ; 0.96(brs. 3H),                                       2.11-2.32(m, 1H), 2.83-3.93(m, 5H),                                           8.04(d, J=13Hz, 1H), 9.00(s, 2H),                                             9.22(s, 1H)      CH.sub.3 CN Et.sub.3                                                          N                          109   H                                                                                ##STR127##                                                                              N Pale brown solid                                                                    Decomposed from 238                                                                  [DMSO-d.sub.6 ] δ; 1.58-2.01(m,                                         2H), 2.73-3.95(m, 5H), 8.05(d, J=12Hz,                                        1H), 8.99(s, 2H), 9.23(s,                                                                      CH.sub.3 CN Et.sub.3                                                          N                          110   H                                                                                ##STR128##                                                                              N Pale brown solid                                                                    Decomposed from 240                                                                  [DMSO-d.sub.6 ] δ; 2.70(brs, 4H)                                        3.64(brs, 4H), 8.14(d, J=14Hz, 1H),                                           9.01(s, 2H), 9.29(s, 1H)                                                                       CH.sub.3 CN Et.sub.3       __________________________________________________________________________                                                       N                      

EXAMPLE 57 Ethyl3-(1,2,5-thiadiazol-3-yl-methylamino)-2-(2,6-dichloro-5-fluoronicotinoyl)acrylate(Compound No.111)

A mixture of ethyl 2,6-dichloro-5-fluoronicotinoylacetate (0.56 g),ethyl orthoformate (0.5 ml) and acetic anhydride (0.57 ml) was stirredat 130° C. for 3 hours. After the solvent was removed in vacuo, asolution of 3-aminomethyl-1, 2,5-thiadiazole (0.24 g) in benzene (5 ml)and methanol (2 ml) was added to the residue. The mixture was stirred atroom temperature for 0.5 hour. The solvent was removed, the residue wasadded with isopropylether (10 ml), and the precipitate was filtrated.The title compound No. 111 was obtained as a pale yellow solid (573 mg).

Melting point: 108°-110° C. ¹ H-NMR(CDCl₃) δ; 0.89 and 1.06(t,J=7 Hz,3H), 3.9-4.15(m,2H), 4.97(d,J=5.8 Hz,2H), 7.37 and 7.43(d,J=7 Hz, 1H),8.35 and 8.39(d,J=14 Hz,1H), 8.56 and 8.58(s, 1H)

EXAMPLE 58 Ethyl7-chloro-6-fluoro-1-(1,2,5-thiadiazol-3-ylmethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate(Compound No.112)

To a solution of compound No.111 (0.55 g) obtained in Example 57 intetrahydrofuran (20 ml), 56 mg of sodium hydride (60% in oil) was added.Then the solution was stirred for 0.5 hour at room temperature. Thesolvent was evaporated, an aqueous 5% citric acid solution (10 ml) wasadded thereto, and extracted with chloroform (50 ml). The extract wasdried over Na₂ SO₄, and the solvent was removed. Isopropylether (10 ml)was added to the residue, and the precipitate was filtrated. The titlecompound No. 112 was obtained as a colorless solid (425 mg).

Melting point: 175-177° C. ¹ H-NMR(CDCl₃) δ; 1.41(t,J=7 Hz,3H),4.41(q,J=7 Hz,2H), 5.79(s,2H), 8.45(d,J=7.3 Hz,1H), 8.73(s,1H),8.83(s,1H)

EXAMPLE 597-Chloro-6-fluoro-1-(1,2,5-thiadiazol-3-ylmethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (Compound No.113)

Compound No.112 (0.4 g) obtained in Example 158 was dissolved in aceticacid (4.5 ml) and 6N-HCl (1.5 ml). The solution was stirred at 100° C.for 2 hours. After cooling, the precipitate was filtrated and washedwith water, ethanol and ether. The title compound No. 113 was obtainedas a pale yellow solid (0.33 g).

Melting point: 231°-232.5° C. ¹ H-NMR(DMSO-d₆) δ; 6.13(s,2H),8.72(d,J=7.8 Hz,1H), 8.93(s,1H), 9.7(s,1H)

EXAMPLE 606-Fluoro-7-(piperazin-1-yl)-1-(1,2,5-thiadiazole-3-ylmethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (Compound No.114)

A mixture of compound No.113 (70 mg) obtained in Example 59, piperazine(26 mg) triethylamine (60 mg) in acetonitrile (2 ml) was stirred at 80°C. for 90 minutes. After cooling, the precipitate was filtrated andwashed with ethanol and ether successively. The title compound No. 114was obtained as a pale orange solid (71 mg).

Melting point: 219.5°-223° C. ¹ H-NMR(DMSO-d₆) δ; 2.64(s,4H),3.57(s,4H), 5.99(s,2H), 8.05(d,J=14 Hz,1H), 8.91(s,1H), 9.25(s,1H)

EXAMPLE 61

Compounds Nos. 115-116 listed in Table 28 were prepared in a similarmanner to Example 60. The data are also shown in Table 28.

                                      TABLE 28                                    __________________________________________________________________________    Compound:                                                                      ##STR129##                                                                   Compound                                                                            Group                   Melting point                                   No.   R.sup.2                                                                          Y          Z  Property                                                                             (°C.)                                                                          .sup.1 H-NMR     Solvent                __________________________________________________________________________    115   H                                                                                 ##STR130##                                                                              N  Pale yellow solid                                                                    208  ∫ 213                                                                       [DMSO-d.sub.6 ] δ; 1.5-1.7(br,                                           1H), 1.7-2.1(br, 1H), 2.9-3.2(m,                                             2H), 5.98(s, 2H), 7.95(d, J=13.7Hz,                                           1H), 8.91(s, 1H), 9.18(s,                                                                      Et.sub.3 N/MeCN        116   H                                                                                 ##STR131##                                                                              N  Pale yellow solid                                                                    178  ∫ 184                                                                       [DMSO-d.sub.6 ] δ; 0.98(d,                                              J=6.8Hz, 3H), 2.2(brs, 1H),                                                   3.1-3.7(m, 5H), 6.00((s, 2H),                                                 7.98(d, J=13Hz, 1H), 8.94(s, 1H),                                             9.21(s, 1H)      "                      __________________________________________________________________________

EXAMPLE 62 Ethyl3-(1,2,5-thiadiazol-3-ylmethylamino)-2-(2,4,5-trifluorobenzoyl)acrylate(Compound No.117)

A mixture of ethyl 2,4,5-trifluorobenzoylacetate (492 mg), ethylorthoformate (0.5 ml) and acetic anhydride (0.57 ml) was stirred at 130°C. for 3 hours. After the solvent was removed in vacuo, a solution of3-aminomethyl-1,2,5-thiadiazole (0.24 g) in benzene (5 ml) was added tothe residue. The mixture was stirred at room temperature for 24 hours.The precipitate was filtrated. The title compound No. 117 was obtainedas a pale yellow solid (530 mg).

Melting point: 167.5°-170° C. ¹ H-NMR(CDCl₃) δ; 0.96 and 1.08(t,J=7Hz,3H), 3.95-4.15(m,2H), 4.91(d,J=6.2 Hz,2H), 6.8-6.95(m,1H),7.15˜7.4(m,1H), 8.14 and 8.23(d,J=13.9 Hz,1H), 8.54 and 8.56(s,1H)

EXAMPLE 63 Ethyl6,7-difluoro-1-(1,2,5-thiadiazol-3-ylmethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.118)

To a solution of compound No.117 (507 mg) obtained in Example 62 intetrahydrofuran (25 ml), 55 mg of sodium hydride (60% in oil) was added.The solution was stirred for 20 minutes at the room temperature, and thesolvent was removed. After addition of an aqueous 5% citric acidsolution (10 ml), extraction was carried out with chloroform (50 ml).The organic phase was dried over Na₂ SO₄ and evaporated. After additionof hexane (10 ml) to the residue, the precipitate was filtrated. Thetitle compound No. 118 was obtained as a pale yellow solid (0.44 g).

Melting point: 198°-201° C. 1H-NMR(CDCl₃) δ; ¹.40 (t,J=7 Hz,3H),4.39(q,J=7 Hz,2H), 5.62(s,2H), 7.29(dd,J=11 Hz,J=6 Hz,1H), 8.27(dd,J=10Hz,J=9 Hz, 1H), 8.56(s,1H), 8.67(s,1H)

EXAMPLE 646,7-Difluoro-1-(1,2,5-thiadiazol-3-ylmethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.119)

Compound No.118 (0.42 g) obtained in Example 63 was dissolved in aceticacid (6 ml) and 6N-HCl (2 ml). The solution was stirred at 100° C. for 2hours. After cooling, the precipitate was filtrated and washed withwater, ethanol and ether. The title compound No. 119 was obtained as acolorless solid (0.325 g).

Melting point: 278°-281.5° C. ¹ H-NMR(DMSO-d₆) δ; 6.19(s,2H),8.1-8.4(m,2H), 8.97(s,1H), 9.31(s,1H)

EXAMPLE 65

Compounds Nos. 120-122 listed in Table 29 were synthesized in a similarmanner to Example 60, proceeding from the corresponding compound No.119.The results are also shown in Table 29.

                                      TABLE 29                                    __________________________________________________________________________    Compound:                                                                      ##STR132##                                                                   Compound                                                                            Group                   Melting point                                   No.   R.sup.2                                                                          Y          Z  Property                                                                             (°C.)                                                                         .sup.1 H-NMR      Solvent                __________________________________________________________________________    120   H                                                                                 ##STR133##                                                                               ##STR134##                                                                      Pale yellow solid                                                                    241  ∫ 245                                                                      [DMSO-d.sub.6 ] δ; 1.7(brs,                                             1H), 1.95(brs, 1H), 3.1-3.7(m, 5H),                                           6.11(s, 2H), 6.51(d, J=7.8Hz, 1H),                                            7.77(d, J=14.2Hz, 1H), 8.97(s, 1H),                                           9.12(s, 1H)       Et.sub.3 N/MeCN        121   H                                                                                 ##STR135##                                                                               ##STR136##                                                                      Pale yellow solid                                                                    225  ∫ 228.5                                                                    [DMSO-d.sub.6 ] δ; 0.97(d,                                              J=7.3Hz, 3H), 2.4(brs,                                                        1H), 3.1-3.8(m, 5H), 6.15((s, 2H),                                            6.57 (d, J=7.8Hz, 1H), 7.81(d,                                                J=14.2Hz, 1H), 9.01(s, 1H), 9.15(s,                                           1H)               "                      122   H                                                                                 ##STR137##                                                                               ##STR138##                                                                      Colorless solid                                                                      261  ∫ 265                                                                      [DMSO-d.sub.6 ] δ; 2.81(s,                                              4H), 3.09(s, 4H), 6.21(s, 2H),                                                7.06(d, J=7.3Hz, 1H), 7.88(d,                                                 J=13.2Hz, 1H), 9.00(s, 1H), 9.23(s,                                           1H)               "                      __________________________________________________________________________

EXAMPLE 66 Ethyl3-(1,2,5-thiadiazol-3-ylmethylamino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylate(Compound No.123)

A mixture of ethyl 2,3,4,5-tetrafluorobenzoylacetate (528 mg), ethylorthoformate (0.5 ml) and acetic anhydride (0.57 ml) was stirred at 130°C. for 3 hours. After the solvent was removed in vacuo, a solution of3-aminomethyl-1,2,5-thiadiazole (0.24 g) in benzene (5 ml) was added tothe residue. The mixture was stirred at room temperature for 40 minutes,and the solvent was removed. To the residue was added 10 ml ofisopropylether. The precipitate was filtrated. The title compound No.123 was obtained as a pale yellow solid (600 mg).

Melting point: 154°-156° C. ¹ H-NMR(CDCl₃) δ; 0.98 and 1.11(t,J=7Hz,3H), 3.95-4.15(m,2H), 4.93(d,J=6.4 Hz,2H), 6.9-7.2(m1H), 8.20 and8.27(d,J=14 Hz,1H), 8.55 and 8.57(s,1H)

EXAMPLE 67 Ethyl6,7,8-trifluoro-1-(1,2,5-thiadiazol-3-ylmethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.124)

To a solution of compound No.123 (0.58 g) obtained in Example 66 intetrahydrofuran (20 ml), 62 mg of sodium hydride (60% in oil) was added.Then the solution was stirred for 0.5 hour at room temperature. Thesolvent was removed, and the residue was added with an aqueous 5% citricacid solution (10 ml). Extraction was carried out with chloroform (50ml). The organic phase was dried (Na₂ SO₄) followed by evaporation. Theresidue was added with isopropylether (10 ml), and the precipitate wasfiltrated. The title compound No. 124 was obtained as a colorless solid(390 mg).

Melting point: 200.5°-203° C. ¹ H-NMR(CDCl₃) δ; 1.41(t,J=7 Hz,3H),4.41(q,J=7 Hz,2H), 5.76(s,2H), 8.1-8.25(m,1H), 8.58(s,2H)

EXAMPLE 686,7,8-Trifluoro-1-(1,2,5-thiadiazol-3-ylmethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.125)

Compound No.124 (0.38 g) obtained in Example 67 was dissolved in aceticacid (4.5 ml) and 6N-HCl (1.5 ml). The solution was stirred at 100° C.for 1.5 hours. After cooling, ethanol (3 ml) was added thereto, and theprecipitate was filtrated, followed by washing with ethanol and ether.The title compound No. 125 was obtained as a colorless solid (0.34 g).

Melting point: 219.5°-222° C. ¹ H-NMR(DMSO-d₆) δ;6.2(s,2H),8.1-8.3(m,1H), 8.96(s,1H), 9.27(s,1H)

EXAMPLE 69

Compounds Nos. 126-128 listed in Table 30 were synthesized in a similarmanner to Example 68, proceeding from the corresponding compound No.125.The data are also shown in Table 30.

                                      TABLE 30                                    __________________________________________________________________________    Compound:                                                                      ##STR139##                                                                   Compound                                                                            Group                 Melting point                                     No.   R.sup.2                                                                         Y          Z Property                                                                             (°C.)                                                                         .sup.1 H-NMR       Solvent                 __________________________________________________________________________    126   H                                                                                ##STR140##                                                                               ##STR141##                                                                     Pale yellow solid                                                                    227  ∫ 231                                                                      [DMSO-d.sub.6 ] δ; 1.4-1.7(m,                                           1H), 1.8-2.0(m, 1H), 3.1-3.8(m, 5H),                                          6.09 6.11(s,     2H), 7.74(d, J=14Hz,                                         1H), 8.91(s, 1H), 9.02(s,                                                                        Et.sub.3 N/CH.sub.3                                                           CN                      127   H                                                                                ##STR142##                                                                               ##STR143##                                                                     Colorless solid                                                                      233.5  ∫ 237                                                                    [DMSO-d.sub.6 ] δ; 0.98(d,                                              J=6Hz, 3H), 2.25(brs, 1H), 3.4-4.9(m,                                         5H), 6.12(s, 2H), 7.75(d, J=14Hz, 1H),                                        8.93(s, 1H), 9.06(s,                                                                             "H)                     128   H                                                                                ##STR144##                                                                               ##STR145##                                                                     Colorless solid                                                                      227  ∫ 228.5                                                                    [DMSO-d.sub.6 ] δ; 2.75(s, 4H),                                         3.11(s, 4H), 6.18(s, 2H), 7.86(d,                                             J=13Hz, 1H), 8.95(s, 1H), 9.14(s,                                                                "H)                     __________________________________________________________________________

EXAMPLE 70 Ethyl3-(1,2,3-thiadiazol-4-ylmethylamino)-2-(2,4,5-trifluorobenzoyl)acrylate(Compound No.129)

A mixture of ethyl 2,4,5-trifluorobenzoylacetate (418 mg), ethylorthoformate (0.43 ml) and acetic anhydride (0.48 ml) was stirred at130° C. for 3 hours. After the solvent was removed in vacuo, a solutionof 4-aminomethyl-1,2,3-thiadiazole (0.2 g) in benzene (5 ml) was addedto the residue. The mixture was stirred for 4 hours. The solvent wasremoved in vacuo. To the residue was added 10 ml of isopropylether. Theprecipitate was filtrated. The title compound No. 129 was obtained as acolorless solid (440 mg).

Melting point: 176°-178° C. ¹ H-NMR(CDCl₃) δ; 0.95 and 1.09(t,J=7 Hz,3H), 3.9-4.15(m,2H), 5.14(d,J=6 Hz,2H), 6.8-7.0(m,1H), 7.1-7.3(m,1H),8.18 and 8.29(d,J=14 Hz,1H), 8.49 and 8.51(s,1H)

EXAMPLE 71 Ethyl6,7-difluoro-1-(1,2,3-thiadiazol-4-ylmethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.130)

To a solution of compound No.129 (0.44 g) obtained in Example 70 intetrahydrofuran (30 ml), 48 mg of sodium hydride (60% in oil) was added.Then the solution was stirred for 3 hours at room temperature. Thesolvent was distilled off, and the residue was added with an aqueous 5%citric acid solution (10 ml), followed by extraction with chloroform (50ml). The organic phase was dried over Na₂ SO₄ and evaporated. Afteraddition of isopropylether (10 ml), the precipitate was filtrated. Thetitle compound No. 130 was obtained as a colorless solid (280 mg).Melting point: 234°-237° C. ¹ H-NMR(DMSO-d₆) δ; 1.30(t,J=7 Hz,3H),4.25(B,J=7 Hz,2H), 6.11(s,2H), 8.0-8.25(m,2H), 9.06(s,1H), 9.36(s,1H)

EXAMPLE 726,7-Difluoro-1-(1,2,3-thiadiazol-4-ylmethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.131)

Compound No.130 (0.28 g) obtained in Example 71 was dissolved in aceticacid (4.5 ml) and 6N-HCl (1.5 ml). The solution was stirred at 100° C.for 2 hours. After cooling, water (30 ml) was added thereto, and theprecipitate was filtrated and washed with water, ethanol and ether. Thetitle compound No. 131 was obtained as a pale yellow solid (0.2 g).

Melting point: 257°-261° C. ¹ H-NMR(DMSO-d₆) δ; 6.30(s,2H), 8.27(dd,J=10Hz,J=9 Hz,1H), 8.40(dd,J=12 Hz,J=6.3 Hz,1H), 9.41(s,1H), 9.44(s,1H)

EXAMPLE 73

Compounds Nos. 132-134 listed in Table 31 were synthesized in a similarmanner to Example 73, proceeding from the corresponding compound No.131.The data are also shown in Table 31.

                                      TABLE 31                                    __________________________________________________________________________    Compound:                                                                      ##STR146##                                                                   Compound                                                                            Group                 Melting point                                     No.   R.sup.2                                                                          Y          Z  Property                                                                           (°C.)                                                                          .sup.1 H-NMR      Solvent                 __________________________________________________________________________    132   H                                                                                 ##STR147##                                                                               ##STR148##                                                                      Yellow solid                                                                       251.5  ∫ 254                                                                     [DMSO-d.sub.6 ] δ; 1.7(brs,                                             1H), 2.0(brs, 1H), 3.1-3.9(m, 5H),                                            6.22(s, 2H), 6.73(brs, 1H), 7.75(d,                                           J=14Hz, 1H), 9.23(s, 1H), 9.39(s,                                                                Et.sub.3 N/CH.sub.3                                                            CN                    133   H                                                                                 ##STR149##                                                                               ##STR150##                                                                      Yellow solid                                                                       Decomposed from 280                                                                   [DMSO-d.sub.6 ] δ; 0.99(brs,                                            3H), 2.2(brs, 1H), 3.1-3.8(m, 5H),                                            6.22(s, 2H), 6.73(brs, 1H), 7.75(d,                                           J=14Hz, 1H), 9.23(s, 1H), 9.38(s,                                                                "H)                    134   H                                                                                 ##STR151##                                                                               ##STR152##                                                                      Yellow solid                                                                       231.5  ∫ 234.5                                                                   [DMSO-d.sub.6 ] δ; 2.84(s, 4H),                                         3.13(s, 4H), 6.31(s, 2H), 7.33(brs,                                           1H), 7.88(d, J=13.7Hz, 1H), 9.34(s,                                           1H), 9.40(s, 1H)   "                      __________________________________________________________________________

EXAMPLE 74 Ethyl2-(2,6-dichloro-5-fluoronicotinoyl)-3-(1,3,4-thiadiazol-2-ylamino)acrylate(Compound No.135)

A mixture of ethyl 2,6-dichloro-5-fluoronicotinoylacetate (4.0 g), ethylorthoformate (3.19 g) and acetic anhydride (4.39 g) was stirred at 130°C. for 2 hours. After the excessive acetic anhydride and ethylorthoformate were removed in vacuo, the residue was dissolved inchloroform (50 ml), to which a methanol solution (100 ml) containing2-amino-1,3,4-thiazole (1.44 g) was added and stirred overnight at roomtemperature. The solvent was removed in vacuo. After dissolved in asmall amount of chloroform, hexane was added thereto for solidifying.The precipitate was filtrated. The title compound No. 135 was obtainedas a pale yellow solid (5.12 g).

Melting point: 137°-140.5° C. ¹ H-NMR(CDCl₃) δ; 0.98 and 1.19(t,J=7 Hz,3H), 4.08-4.27(m,2H), 7.45 and 7.58(d,J=6.8 Hz, 1H), 8.68-9.04(m,2H)

EXAMPLE 75 Ethyl6-fluoro-7-chloro-1-(1,3,4-thiadiazol-2-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate(Compound No.136)

A solution of compound No.135 (5.12 g) obtained in Example 74 andpotassium carbonate (1.81 g) in dimethylformamide (20 ml) was stirredfor 15 minutes at 90° C. After addition of an aqueous 5% citric acidsolution (500 ml), the precipitate was filtrated and washed with water,ethanol and ether successively. The title compound No. 136 was obtainedas a pale yellow solid (3.83 g).

Melting point: 201°-203° C. ¹ H-NMR(CDCl₃) δ; 1.44(t,J=7 Hz,3H),4.45(q,J=7 Hz,2H), 8.57(d,J=6.8 Hz,1H), 9.21(s,1H), 10.02(s,1H)

EXAMPLE 76 Ethyl7-(pyrrolidin-1-yl)-6-fluoro-1-(1,3,4-thiadiazole-2-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate(Compound No.137)

A mixture of compound No.136 (100 mg)obtained in Example 75, pyrrolidine(22 mg) and triethylamine (33 mg) in acetonitrile (10 ml) was stirred at80° C. for 60 minutes. The precipitate was filtrated and washed withethanol. The title compound was obtained as a pale yellow solid (79 mg).

Melting point: 238°-242° C. ¹ H-NMR(DMSO-d₆) δ; 1.32(t,J=7 Hz,3H),1.99(brs,4H), 3.74(brs,4H), 4.29(q,J=7 Hz,2H), 7.84(d,J=12.7 Hz,1H),9.48(s,1H), 9.52(s,1H)

EXAMPLE 777-(Pyrrolidin-1-yl)-6-fluoro-1-(1,3,4-thiadiazole-2-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, sodium salt (Compound No.138)

Compound No.137 (0.05 g) obtained in Example 76 was suspended intetrahydrofuran (20 ml), to which an aqueous 1N-NaOH solution (0.13 ml)was added. The solution was stirred at room temperature for 3 days.After evaporation of the solvent, chloroform was added. The precipitatewas filtrated. The title compound No. 138 was obtained as a pale brownsolid (42 mg).

Melting point: 253°-263° C. ¹ H-NMR(DMSO-d₆) δ; 1.78(s,4H),7.68(d,J=12.7 Hz,1H), 9.73(s,1H), 9.87(s,1H)

EXAMPLE 78

Compounds No. 139-140 were synthesized in a similar manner to Example77.

The name of compound No. 139, its property, melting point and ¹ H-NMRdata are as follows: Ethyl6-fluoro-7-(4-methylpiperazin-1-yl)-1-(1,3,4-thiadiazol-2-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate(Compound No.139).

Pale orange solid.

Melting point: 204°-206° C. ¹ H-NMR(DMSO-d₆) δ; 1.31(t,J=7 Hz,3H),2.24(s,3H), 2.50(brs,4H), 3.77(brs,4H), 4.28(q,J=7 Hz,2H), 8.04(d,J=13.2Hz, 1H), 9.46(s,1H), 9.59(s,1H)

The name of compound No. 140, its property, melting point and ¹ H-NMRdata are as follows:6-Fluoro-7-(4-methylpiperazin-1-yl)-1-(1,3,4-thiadiazol-2-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine- 3-carboxylic acid, sodium salt (Compound No.140)

Pale orange solid.

Melting point: 241°-246° C., decomposed ¹ H-NMR(DMSO-d₆) δ; 2.13(s,3H),2.24(s,4H), 7.77(d,J=13.7 Hz,1H), 9.74(s,1H), 9.90(s,1H)

EXAMPLE 79 Ethyl6,7-difluoro-1-(1,3,4-thiadiazol-2-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.141)

A mixture of ethyl 2,4,5-trifluorobenzoylacetate (9.84 g), ethylorthoformate (10 ml) and acetic anhydride (17 ml) was stirred at 130° C.for 12 hours. After the solvent was removed in vacuo, a solution of2-amino-1,3,4-thiadiazole (4.55 g) and methanol (30 ml) in chloroform(40 ml) was added to the residue. The mixture was stirred at roomtemperature for 24 hours. The solvent was removed in vacuo. The residuewas purified by chromatography on silicagel (chloroform/ethyl acetate1:1 as an eluent) to obtain an intermediate of yellow oil (14 g). Asolution of this oily material (14 g) and potassium carbonate (5.4 g) inN,N-dimethylformamide (40 ml) was stirred for 20 minutes at 100° C. Thesolvent was removed in vacuo. After addition of water (200 ml) to theresidue, the precipitate was filtrated and washed with water, ethanoland ether successively. The title compound No. 141 was obtained as ayellow solid (9.4 g).

Melting point: 235°-238° C. ¹ H-NMR(DMSO-d₆) δ; 1.28(t,J=7 Hz,3H),4.24(q,J=7 Hz,2H), 7.56(dd,J=11.7 Hz, J=6.3 Hz,1H), 8.14(dd,J=9 Hz,J=10Hz,1H), 8.78(s,1H), 9.88(s,1H)

EXAMPLE 806,7-Difluoro-1-(1,3,4-thiadiazol-2-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.142)

Compound No.141 (0.5 g) obtained in Example 79 was dissolved intetrahydrofuran (70 ml). To this solution were added 3 ml of water and0.75 ml of 2N-NaOH, then-stirred at room temperature for 20 minutes.After evaporation of tetrahydrofuran in vacuo, the residue wasneutralized with an aqueous 20% acetic acid solution. The precipitatewas filtrated and washed with water, ethanol and ether successively. Thetitle compound No. 142 was obtained as a yellow solid (0.38 g).

Melting point: 233°-236° C. ¹ H-NMR(DMSO-d₆) δ; 7.13(dd,J=12 Hz,J=6.8Hz,1H), 8.15(dd,J=9 Hz,J=10 Hz,1H), 9.87(s,1H), 10.0(s,1H)

EXAMPLE 81 Ethyl2-(2,4,5-trifluorobenzoyl)-3-(5-methyl-1,3,4-thiadiazol-2-ylamino)acrylate(Compound No.143)

A mixture of ethyl 2,4,5-trifluorobenzoylacetate (2.18 g), ethylorthoformate (1.97 g) and acetic anhydride (4.12 g) was stirred at 130°C. for 3 hours. After the excessive acetic anhydride and ethylorthoformate were removed in vacuo, the residue was dissolved in 50 mlbenzene, to which a solution of 2-amino-5-methyl-1,3,4-thiadiazole (1.00g) in methanol (150 ml) was added. The mixture was stirred at roomtemperature for 24 hours. The solvent was removed in vacuo. The residuewas purified by chromatography on silicagel (chloroform/ethyl acetate10:1 as an eluent). The title compound No. 143 was obtained as acolorless solid (1.78 g).

Melting point: 147°-151° C. ¹ H-NMR(CDCl₃) δ; 1.04 and 1.19(t,J=7Hz,3H); 2.73 and 2.75(s,1H); 4.10-4.28(m,2H); 6.87-7.06(m,1H); 7.30-7.42and 7.48-7.62(m,1H); 8.34 and 8.70(d,J=12.7 Hz,1H); 11.31(d,J=12.2Hz,1H)

EXAMPLE 82

Ethyl6,7-difluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.144)

To a solution of compound No.143 (1.5 g) obtained in Example 81 intetrahydrofuran (40 ml), 0.20 g of sodium hydride (60% in oil) wasadded. Then the solution was stirred for 2 days at room temperature.Tetrahydrofuran was evaporated. The residue was dissolved in chloroform(80 ml) and washed with 5% citric acid solution (10 ml). The aqueoussolution was extracted with chloroform (80 ml), followed by dehydrationwith Glauber's salt. Chloroform was evaporated, and the residue waspurified by chromatography on silicagel (chloroform/ethyl acetate 5:1 asan eluent). The title compound No. 144 was obtained as a pale yellowsolid (0.85 g).

Melting point: 170°-173° C. ¹ H-NMR(CDCl₃) δ; 1.40(t,J=7.3 Hz,3H);2.96(s,3H); 4.39(q,J=7 Hz,2H); 7.35(dd,J=10.7 Hz,6.3 Hz,1H);8.28(dd,J=8.8 Hz,10 Hz,1H); 8.58(s,1H)

EXAMPLE 836,7-Difluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, sodium salt (Compound No.145)

Compound No.144 (0.1 g) obtained in Example 82 was dissolved intetrahydrofuran (10 ml) and 1N-NaOH (0.3 ml). The solution was stirredat room temperature overnight. After addition of chloroform, theprecipitate was filtrated, followed by washing with chloroform. Thetitle compound No. 145 was obtained as a pale yellow solid (77 mg).

Melting point: Colored from 255° C., decomposed 295° C. ¹ H-NMR(DMSO-d₆)δ; 2.80(s,3H); 7.02(dd,J=12.7 Hz,6.8 Hz,1H); 7.92(dd, J=10.7 Hz,9.3Hz,1H); 9.97(s,1H)

EXAMPLE 84 Ethyl2-(2,6-dichloro-5-fluoronicotinoyl)-3-(5-methyl-1,3,4-thiadiazol-2-ylamino)acrylate(Compound No.146)

A mixture of ethyl 2,6-dichloro-5-fluoronicotinoylacetate (4.00 g),ethyl orthoformate (3.18 g) and acetic anhydride (4.38 g) was stirred at130° C. for 2 hours. After the excessive acetic anhydride and ethylorthoformate were removed in vacuo, the residue was dissolved in 40 mlchloroform, to which a solution of 2-amino-5-methyl-1,3,4-thiadiazole(1.61 g) in methanol (180 ml) was added. The mixture was stirred at roomtemperature overnight. The solvent was removed in vacuo. The residue waspurified by chromatography on silicagel (chloroform/ethyl acetate 10:1then 5:1 as an eluent). The title compound No. 146 was obtained as apale yellow solid (4.37 g).

Melting point: 142°-152° C. decomposed ¹ H-NMR(CDCl₃) δ; 0.97 and1.17(t,J=7 Hz,3H); 2.76 and 2.87(s,3H); 4.07-4.25(m,2H); 7.44 and7.56(d,J=7 Hz,1H); 8.63 and 8.87(s,1H)

EXAMPLE 85 Ethyl6-fluoro-7-chloro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate(Compound No.147)

To a solution of compound No.146 (4.1 g) obtained in Example 84 intetrahydrofuran (100 ml), 0.49 g of sodium hydride (60% in oil) wasadded. Then the solution was stirred for 1 day at room temperature.Tetrahydrofuran was removed and the residue was dissolved in chloroform(200 ml), followed by washing with 5% citric acid solution and driedover Na₂ SO₄. Chloroform was evaporated, and the residue was suspendedin hexane, and the solid was filtrated. The title compound No. 147 wasobtained as an orange solid (3.53 g).

Melting point: 159°-162° C. ¹ H-NMR(CDCl₃) δ; 1.43(t,J=7 Hz,3H);2.86(s,3H); 4.44(q,J=7 Hz,2H); 8.55(d,J=7.3 Hz,1H); 9.89(s,1H)

EXAMPLE 86 Ethyl7-(3-(S)-aminopyrrolidin-1-yl)-6-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate(Compound No.148)

A mixture of compound No.147 (100 mg), 3-(S)aminopyrrolidine (33 mg) andtriethylamine (39 mg) in acetonitrile (10 ml) was stirred at 80° C. for60 minutes. After cooling, the precipitate was filtrated and washed withethanol. The title compound No. 148 was obtained as a pale orange solid(73 mg).

Melting point: 265°-268° C. ¹ H-NMR(D₂ O) δ; 1.35(t,J=7 Hz,3H);2.71(s,3H);4.26(q,J=7 Hz,2H); 7.59(d,J=12.2 Hz,1H); 8.90(s,1H)

EXAMPLE 877-(3-(S)-Aminopyrrolidin-1-yl)-6-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, sodium salt (Compound No.149)

Compound No.148 (0.05 g) obtained in Example 86 was dissolved in water(3 ml) and 1N-NaOH (0.1 ml). The solution was stirred at roomtemperature for 24 hours. After evaporation of water, chloroform wasadded. The precipitate was filtrated. The title compound No. 149 wasobtained as a pale orange solid (18 mg).

Melting point: Colored from 200° C., decomposed 280° C. ¹ H-NMR(D₂ O) δ;2.0-2.3(brs,1H); 2.43(s,3H); 3.6(brs,1H); 7.25 (d,J=12.7 Hz,1H);8.85(s,1H)

EXAMPLE 88

Ethyl2-(2,6-dichloro-5-fluoronicotinoyl)-3-(5-trifluoromethyl-1,3,4-thiadiazol-2-ylamino)acrylate(Compound No.150)

A mixture of ethyl 2,6-dichloro-5-fluoronicotinoylacetate (2.8 g), ethylorthoformate (2.6 ml) and acetic anhydride (2.8 ml) was stirred at 130°C. for 6 hours. After the solvent was removed in vacuo, a solution of2-amino-5-trifluoromethyl-1,3,4-thiadiazole (1.69 g) in chloroform (20ml) and ethanol (8 ml) was added to the residue. The mixture was stirredat room temperature for 4 hours. The solvent was removed in vacuo. Theresidue was purified by chromatography on silicagel (chloroform/ethylacetate 50:1 as an eluent). The title compound No. 150 was obtained as ayellow waxy solid (4.5 g).

Melting point: 73°-76° C. ¹ H-NMR(CDCl₃) δ; 0.98 and 1.19(t,J=7 Hz,3H),4.05-4.25(m,2H), 7.47 and 7.62(d,J=7.4 Hz,1H), 8.67 and 8.91 (d,J=12Hz,1H)

EXAMPLE 89 Ethyl7-chloro-6-fluoro-1-(5-trifluoromethyl-1,3,4-thiadiazole-2-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate(Compound No.151)

A solution of compound No.150 (4.3 g) obtained in Example 88 and sodiumhydrogencarbonate (0.79 g) in N,N-dimethylformamide (30 ml) was stirredfor 15 minutes at 100° C. The solvent was removed in vacuo, andextracted with chloroform (200 ml). The organic phase was washed withwater. The organic layer was dried over Na₂ SO₄ and evaporated. Theresidue was added with ether (20 ml) and the precipitate was filtrated.The title compound No. 151 was obtained as a colorless solid (3.2 g).

Melting point: 177.5°-178.5° C. ¹ H-NMR(CDCl₃) δ; 1.44(t,J=7 Hz,3H),4.46(q,J=7 Hz,2H), 8.58(d,J=6.8 Hz,1H), 10.0(s,1H)

EXAMPLE 907-Chloro-6-fluoro-1-(5-trifluoromethyl-1,3,4-thiadiazole-2-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (Compound No.152)

Compound No.151 (30 mg) obtained in Example 89 was dissolved in amixture of acetic acid (2 ml) and HCl (0.5 ml). The solution was stirredat 100° C. for 0.5 hour. After cooling and addition of water (4 ml), theprecipitate was filtrated and washed with ethanol, ether and n-hexane.The title compound No. 152 was obtained as a colorless solid (13 mg).

Melting point: 232°-237° C. ¹ H-NMR(DMSO-d₆) δ; 8.81(d,J=7 Hz,1H),9.79(s,1H)

EXAMPLE 916-Fluoro-7-(pyrrolidin-1-yl)-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (Compound No.153)

A mixture of compound No.151 (200 mg) obtained in Example 89 andpyrrolidine (67 mg) in chloroform (5 ml) was stirred at room temperaturefor 15 minutes. After evaporation of the solvent, ethanol (10 ml) wasadded. The precipitate was filtrated to obtain a colorless solid (170mg). 50 mg of the obtained solid was taken and dissolved intetrahydrofuran (3 ml), to which 6N-HCl (0.3 ml) was added. Afterstirring for 1 day at room temperature, the precipitate was filtratedand washed with water, ethanol and ether. The title compound No. 153 wasobtained as a yellow solid (30 mg).

Melting point: 239.5°-241° C. ¹ H-NMR(DMSO-d₆) δ; 2.04(brs,4H),3.84(brs,4H), 8.04(d,J=12.7 Hz,1H), 9.63(s,1H)

EXAMPLE 92 Ethyl2-(2,4,5-trifluorobenzoyl)-3-(5-trifluoromethyl-1,3,4-thiadiazol-2-ylamino)acrylate(Compound No.154)

A mixture of ethyl 2,4,5-trifluorobenzoylacetate (2.46 g), ethylorthoformate (2.6 ml) and acetic anhydride (2.8 ml) was stirred at 130°C. for 6 hours. After the solvent was removed in vacuo, a solution of2-amino-5-trifluoromethyl-1,3,4-thiadiazole (1.69 g) and ethanol (5 ml)in chloroform (20 ml) was added to the residue. The mixture was stirredat room temperature for 24 hours. The solvent was removed in vacuo. Theresidue was purified by chromatography on silicagel (chloroform/ethylacetate 50:1 as an eluent). The title compound No. 154 was obtained as ayellow oil (2.3 g).

¹ H-NMR(CDCl₃) δ; 1.05 and 1.21(t,J=7 Hz,3H), 4.1-4.3(m,2H),6.85-7.05(m,1H), 7.35-7.45 and 7.52-7.7(m,1H), 8.36-8.73(d,J=12 Hz,1H)

EXAMPLE 93 Ethyl6,7-difluoro-1-(5-trifluoromethyl-1,3,4-thiadiazole-2-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.155)

A solution of compound No.154 (2.3 g) obtained in Example 92 andpotassium carbonate (0.75 g) in N,N-dimethylformamide (20 ml) wasstirred for 10 minutes at 100° C. The solvent was removed in vacuo.After extraction with chloroform, the organic phase was washed withwater, dried (Na₂ SO₄) and evaporated. After addition of hexane (50 ml)to the residue, the precipitate was filtrated. The title compound wasobtained as a red solid (1.1 g)

Melting point: 130°-136° C. ¹ H-NMR(CDCl₃) δ; 1.37(t,J=7 Hz,3H),4.33(q,J=7 Hz,2H), 7.46(dd, J=10.7 Hz,J=6.4 Hz,1H), 8.13(dd,J=9.8Hz,J=8.5 Hz,1H), 8.55(s,1H)

EXAMPLE 946,7-Difluoro-1-(5-trifluoromethyl-1,3,4-thiadiazole-2-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.156)

Compound No.155 (30 mg) obtained in Example 93 was dissolved in amixture of acetic acid (2 ml) and HCl (0.5 ml). The solution was stirredat 100° C. for 40 minutes. After allowed to be cooled, water (4 ml) wasadded to the reaction mixture, and the precipitate was filtrated andwashed with ethanol, ether and n-hexane. The title compound No. 156 wasobtained as a pale orange solid (18 mg).

Melting point: 272°-276° C. ¹ H-NMR(DMSO-d₆) δ; 7.96(dd,J=12 Hz,J=6Hz,1H), 8.33(dd,J=9 Hz,J=10 Hz,1H), 9.25 (s,1H)

EXAMPLE 95 Ethyl3-(1,2,5-thiadiazole-3-ylamino)-2-(2-methyl-3,4,6-trifluorobenzoyl)acrylate(Compound No.157)

Compound No. 157 (colorless needles) was prepared in a similar manner toExample 17, proceeding from the corresponding compounds ethyl2-methyl-3,4,6,-trifluorobenzoylacetate, ethyl orthoformate, aceticanhydride and 3-amino-1,2,5-thiadiazole hydrochloride.

Melting point: 134°-136° C. ¹ H-NMR(CDCl₃) δ; 1.14(t,J=7 Hz,3H),2.22(d,J=3 Hz,3H), 4.13(q,J=7 Hz,2H), 6.80(dt,J=10 Hz,6 Hz,1H),8.36(s,1H), 9.00(d,J=12 Hz,1H)

EXAMPLE 96 Ethyl5-methyl-6,7-difluoro-1-(1,2,5-thiadiazol-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.158)

Compounds No. 158 which is a pale yellow solid was prepared in a similarmanner to Example 18, proceeding from the corresponding compound No.157.

Melting point: 208°-213° C. ¹ H-NMR(CDCl₃) δ; 1.38(t,J=7 Hz,3H),2.89(d,J=3 Hz,3H), 4.39(q,J=7 Hz,2H), 6.86(dd,J=11 Hz,7 Hz,1H),8.46(s,1H), 8.79(s,1H)

EXAMPLE 975-Methyl-6,7-difluoro-1-(1,2,5-thiadiazol-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.159)

Compounds No. 159 which is a colorless solid was prepared in a similarmanner to Example 19, proceeding from the corresponding compound No.158.

Melting point: 264°-268° C. decomposed ¹ H-NMR(DMSO-d₆) δ; 2.87(d,J=3Hz,3H), 7.58(dd,J=7 Hz,J=12 Hz,1H), 9.07(s,1H),9.22(s,1H)

EXAMPLE 98

Compounds Nos. 160-163 listed in Tables 32 and 33 were synthesized in asimilar manner to Example 4, proceeding from the compound No.159obtained in Example 97.

                                      TABLE 32                                    __________________________________________________________________________    Compound:                                                                      ##STR153##                                                                           Group                                                                 Compound No.                                                                          R.sup.2                                                                          Y         Z Property                                                                              Melting Point (°C.)                                                              .sup.1 H-NMR     Solvent             __________________________________________________________________________    160     CH.sub.3                                                                          ##STR154##                                                                              ##STR155##                                                                     Colorless solid                                                                       194  ∫ 198                                                                         [DSMO-d.sub.6 ] δ;                                                      2.64(brs, 4H), 2.80(d, J=3Hz,                                                 3H), 3.03(brs, 4H), 6.52(d,                                                   J=7Hz, 1H), 8.89(s, 1H), 9.30(s,                                              1H)              CH.sub.3 CN                                                                   Et.sub.3 N          161     CH.sub.3                                                                          ##STR156##                                                                              ##STR157##                                                                     Colorless solid                                                                       243  ∫ 247                                                                         [DMSO-d.sub.6 ] δ; 2.20(s,                                              3H), 2.42(brs, 4H), 2.80(d,                                                   J=3Hz, 3H), 3.12(brs, 4H),                                                    6.57(d, J=8Hz, 1H), 8.93(s, 1H),                                              .31(s, 1H)       CH.sub.3 CN                                                                   Et.sub.3            __________________________________________________________________________                                                              N               

                                      TABLE 33                                    __________________________________________________________________________    Compound                                                                            Group                                                                   No.   R.sup.2                                                                          Y          Z Property                                                                             Melting Point (°C.)                                                              .sup.1 H-NMR       Solvent             __________________________________________________________________________    162   CH.sub.3                                                                          ##STR158##                                                                               ##STR159##                                                                     Pale yellow solid                                                                    205  ∫ 208                                                                         [DMSO-d.sub.6 ] δ; 1.58-1.72(                                           m, 1H), 1.88-2.03(m,                                                          1H), 2.77(brs, 3H),                                                           3.05˜3.15(m,                                                            1H), 3.28-3.60(m), 5.99(d, J=8Hz,                                             1H), 8.82(s, 1H), 9.29(s,                                                                        CH.sub.3 CN                                                                   Et.sub.3 N          163   CH.sub.3                                                                          ##STR160##                                                                               ##STR161##                                                                     Pale yellow solid                                                                    242  ∫ 245                                                                         [DMSO-d.sub.6 ] δ; 0.94(d,                                              J=7Hz, 3H), 2.09-2.23(m, 1H),                                                 2.75(brs, 1H), 3.10-3.62(m),                                                  5.59(d, J= 8Hz, 1H), 8.82(s, 1H),                                             9.28(s, 1H)        CH.sub.3 CN                                                                   Et.sub.3            __________________________________________________________________________                                                              N               

EXAMPLE 99 Ethyl7-chloro-6-fluoro-1-(1,2,4-thiadiazol-5-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate(Compound No.164)

A mixture of ethyl 2,6-dichloro-5-fluoronicotinoylacetate (4.2 g), ethylorthoformate (3.9 ml) and acetic anhydride (4.3 ml) was stirred at 135°C. for 2 hours. After the solvent was removed in vacuo, the residue wasadded with chloroform (20 ml) and ethanol (10 ml).5-Amino-1,2,4-thiadiazole (1.51 g) was added thereto and allowed toreact for 8 hours. The solvent was removed. The residue was added withn-hexane, and the precipitate was filtrated. 4.1 g of a yellow solid wasobtained. 3.5 g was taken therefrom and dissolved in dimethylformamide(35 ml). 0.36 g of sodium hydride (60% in oil) was added thereto andallowed to react at 100° C. for 5 minutes. The solvent was removed.After addition of water to the residue, the insoluble matter wasfiltrated and washed with water, ethanol, ether and n-hexanesuccessively. The title compound No. 164 was obtained as a pale yellowsolid (2.5 g).

Melting point: 203°-206° C. ¹ H-NMR(CDCl₃) δ; 1.34(t,J=7 Hz,3H),4.34(q,J=7 Hz,2H), 8.71(d,J=8 Hz,1H), 8.85(s,1H), 9.71(s,1H)

EXAMPLE 1007-Chloro-6-fluoro-1-(1,2,4-thiadiazol-5-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (Compound No.165)

Compound No. 164 (1.1 g) obtained in Example 99 was dissolved in amixture of tetrahydrofuran (40 ml) and c-HCl (10 ml). The solution wasstirred at 80° C. for 1.5 hour. After the solvent was removed in vacuo,the precipitate was filtrated and washed with ethanol, ether andn-hexane. The title compound No. 165 was obtained as a slightly yellowsolid.

Melting point: 278°-282° C. ¹ H-NMR(DMSO-d₆) δ; 8.82(d,J=7 Hz,1H),8.88(s,1H), 9.81(s,1H)

EXAMPLE 101

Compounds Nos. 166-167 listed in Table 34 were synthesized in a similarmanner to Example 41, proceeding from the compound No.164 obtained inExample 99.

                                      TABLE 34                                    __________________________________________________________________________    Compound:                                                                      ##STR162##                                                                   Compound                                                                             Group                                                                  No.    R.sup.2                                                                         Y          Z Property                                                                             Melting Point (°C.)                                                              .sup.1 H-NMR       Solvent             __________________________________________________________________________    166    H                                                                                ##STR163##                                                                              N Dim yellow solid                                                                     Colored from 285, decomposed                                                            [DMSO-d.sub.6 ] δ; 2.28-2.50(                                           m, 2H), 4.05-4.18(m, 3H), 8.18(d,                                             J=13Hz, 1H), 8.49(brs, 3H),                                                   9.53(s, 1H), 9.73(s,                                                                              ##STR164##         167    H                                                                                ##STR165##                                                                              N Pale yellow solid                                                                    Colored from 225, decomposed                                                            [DMSO-d.sub.6 ] δ; 1.18(d,                                              J=6Hz, 3H), 1.49-1.57(m, 1H),                                                 1.69-1.77(m, 1H), 3.80-4.48(s,                                                4H), 8.19(d, J=13Hz, 1H), 8.87(s,                                             1H), 9.75(s, 1H)                                                                                  ##STR166##         __________________________________________________________________________

EXAMPLE 102

Compounds Nos. 168-170 listed in Table 35 were synthesized in a similarmanner to Example 11, proceeding from the compound No.165 obtained inExample 100.

                                      TABLE 35                                    __________________________________________________________________________    Compound:                                                                      ##STR167##                                                                   Compound                                                                            Group                                                                   No.   R.sup.2                                                                          Y          Z  Property                                                                             Melting Point (°C.)                                                              .sup.1 H-NMR     Solvent              __________________________________________________________________________    168   H                                                                                 ##STR168##                                                                              N  Dim yellow solid                                                                     Colored from 290, decomposed                                                            [DMSO-d.sub.6 ] δ; 2.49(s,                                              3H), 2.84(brs, 4H), 8.38(d,                                                   J=13Hz, 1H), 8.89(s, 1H), 9.83(s,                                             1H)                                                                                             ##STR169##          169   H                                                                                 ##STR170##                                                                              N  Pale brown solid                                                                     Colored from 280, decomposed                                                            [DMSO-d.sub.6 ] δ; 3.43(brs,                                             4H), 4.38(brs, 4H), 8.37(d,                                                  J=13Hz, 1H), 8.90(s, 1H),                                                     9.20(brs, 2H), 9.83(s,                                                                          ##STR171##          170   H                                                                                 ##STR172##                                                                              N  Dim yellow solid                                                                     Colored from 278, decomposed                                                            [DMSO-d.sub.6 ] δ; 4.30(brs,                                             1H), 4.63-4.85(m, 4H), 8.23(d,                                               J=13Hz, 1H), 8.68(brs, 3H),                                                   8.88(s, 1H), 9.74(s,                                                                            ##STR173##          __________________________________________________________________________

EXAMPLE 103 Ethyl6,7-difluoro-1-(1,2,4-thiadiazol-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.171)

A mixture of ethyl 2,4,5-trifluorobenzoylacetate (3.7 g), ethylorthoformate (3.9 ml) and acetic anhydride (4.3 ml) was stirred at 135°C. for 3 hours. After the solvent was removed in vacuo, a solution of5-amino-1,2,4-thiadiazole (1.51 g) in chloroform (20 ml) and ethanol (10ml) was added to the residue. The mixture was stirred at roomtemperature for 8 hours. The solvent was removed. The residue waspurified by column chromatography on silicagel (chloroform/ethyl acetate4:1 as an eluent) to obtain 4.4 g of a yellow oil. A solution of thisoil (4 g) and sodium hydride(0.45 g) in dimethylformamide (40 ml) wasstirred for 5 minutes at 100° C. The solution was removed. Chloroformand water were added to the residue, and the organic phase wasextracted. After evaporation of the solvent, the residue was added withethanol, and the precipitate was filtrated, washed with ethanol, etherand n-hexane successively. The title compound No. 171 was obtained as ayellow solid (1.5 g).

Melting point: 149°-152° C. ¹ H-NMR(CDCl₃) δ;1.42(t,J=7 Hz,3H),4.43(q,J=7 Hz,2H), 8.23-8.33(m,2H), 8.71(s,1H), 8.79(s,1H)

EXAMPLE 1046,7-Difluoro-1-(1,2,4-thiadiazol-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.172)

Compound No.171 (0.7 g) was dissolved in a mixture of tetrahydrofuran(28 ml) and c-HCl (7 ml). The solution was stirred at 80° C. for 1 hour.After evaporation of the solvent, the residue was added with ethanol.The precipitate was filtrated and washed with ethanol, ether andn-hexane. The title compound No. 172 was obtained as a brown solid (0.56g).

Melting point: 212°-216° C. ¹ H-NMR(DMSO-d₆) δ; 7.99(dd,J=6 Hz,J=12Hz,1H), 8.34(dd,J=9 Hz,J=10 Hz,1H), 9.08(s,2H)

EXAMPLE 105

Compound No. 173 listed in Table 36 was prepared in a similar manner toExample 4, proceeding from the compound No.172.

                                      TABLE 36                                    __________________________________________________________________________    Compound:                                                                      ##STR174##                                                                           Group                                                                 Compound No.                                                                          R.sup.2                                                                         Y      Z Property Melting Point (°C.)                                                              .sup.1 H-NMR        Solvent             __________________________________________________________________________    173     H                                                                                ##STR175##                                                                           ##STR176##                                                                     Pale brown solid                                                                       145  ∫ 147                                                                         [DMSO-d.sub.6 ] δ; 1.93(brs,                                            4H), 3.48(brs, 4H), 6.71(d, J=7Hz,                                            1H), 7.85(d, J=15Hz, 1H), 8.92(s,                                             1H), 9.06(s, 1H)    MeCN Et.sub.3       __________________________________________________________________________                                                              N               

EXAMPLE 106 Ethyl2-(2,6-dichloro-5-fluoronicotinoyl)-3-(1H-tetrazol-5-ylamino)acrylate(Compound No.174)

A mixture of ethyl 2,6-dichloro-5-fluoronicotinoylacetate (5.6 g), ethylorthoformate (5.2 ml) and acetic anhydride (5.6 ml) was stirred at 130°C. for 4 hours. After the solvent was removed in vacuo, a solution of5-amino-1H-tetrazole (1.7 g) in benzene (20 ml) and methanol (40 ml) wasadded to the residue. The mixture was stirred at room temperature for 5hours. The solvent was removed. After addition of hexane (100 ml.) tothe residue, stirring was carried out for 1 hour. The precipitate wasfiltrated. The title compound No. 174 was obtained as a colorless solid(6.5 g).

Melting point: 150.5°-152° C. ¹ H-NMR(DMSO-d₆) δ; 1.05(t,J=7 Hz,3H),3.9-4.15(m,2H), 7.93(s,1H), 8.24 and 8.60(d,J=8 Hz,1H), 8.79(s,1H)

EXAMPLE 107 Ethyl7-chloro-6-fluoro-1-(1H-tetrazol-5-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate(Compound No.175)

A solution of compound No.174 (3 g) obtained in Example 106 andpotassium carbonate (1.1 g) in N,N-dimethylformamide (20 ml) was stirredfor 1 hour at 110° C. The solution was removed in vacuo. After additionof 6N-HCl (30 ml) to the residue, the precipitate was filtrated andwashed with water, ethanol and ether successively. The title compoundNo. 175 was obtained as a yellow solid (2.7 g).

Melting point: 202°-207° C. ¹ H-NMR(DMSO-d₆) δ; 1.28(t,J=7 Hz,3H),4.26(q,J=7 Hz,2H), 8.57(d,J=7.7 Hz,1H), 8.92(s,1H)

EXAMPLE 1087-Chloro-6-fluoro-1-(1H-tetrazol-5-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (Compound No.176)

Compound No.175 (1.2 g) obtained in Example 107 was dissolved in amixture of acetic acid (5 ml) and 6N-HCl (5 ml). The solution wasstirred at 100° C. for 2 hours. After evaporation of the solvent invacuo, 5 ml of ethanol was added to the residue. The precipitate wasfiltrated and washed with ether. The title compound No. 176 was obtainedas a pale yellow solid (0.68 g).

Melting point: 270° C. or more, colored and decomposed ¹ H-NMR(DMSO-d₆)δ; 8.74(d,J=7.2 Hz,1H), 9.07(s,1H)

EXAMPLE 109

Compounds No. 177 listed in Table 37 was synthesized in a similar mannerto Example 4, proceeding from the compound No.176 obtained in Example108.

                                      TABLE 37                                    __________________________________________________________________________    Compound:                                                                      ##STR177##                                                                   Compound                                                                             Group                                                                  No.    R.sup.2                                                                         Y          Z Property                                                                             Melting Point (°C.)                                                              .sup.1 H-NMR      Solvent              __________________________________________________________________________    177    H                                                                                ##STR178##                                                                              N Pale yellow solid                                                                    Colored from 250, decomposed                                                            [DMSO-d.sub.6 ] δ; 1.5-1.8(m,                                            1H), 1.8-2.05(m, 1H), 2.7-3.2(m,                                             4H), 8.0(d, J=12.8Hz, 1H), 8.44(s,                                            1H)               MeCN + DMF                                                                    Et.sub.3             __________________________________________________________________________                                                             N                

EXAMPLE 110

Compounds Nos. 178-179 listed in Table 38 were synthesized in a similarmanner to Example 11, proceeding from the compound No.177 obtained inExample 109.

                                      TABLE 38                                    __________________________________________________________________________    Compound:                                                                      ##STR179##                                                                   Compound                                                                             Group                                                                  No.    R.sup.2                                                                         Y          Z Property                                                                           Melting Point (°C.)                                                              .sup.1 H-NMR      Solvent                __________________________________________________________________________    178    H                                                                                ##STR180##                                                                              N Colorless solid                                                                    300 or more                                                                             [DMSO-d.sub.6 ] δ; 3.14(brs,                                            4H), 3.82(brs, 4H), 8.24(d,                                                   J=12.8Hz, 1H), 8.94(s,                                                        1H), 9.57(brs, 2H),                                                                              ##STR181##            179    H                                                                                ##STR182##                                                                              N Colorless solid                                                                    Colored from 285, decomposed                                                            [DMSO-d.sub.6 ] δ; 2.74(s,                                              3H), 3.10(brs, 2H), 3.3-3.6(br, 4H),                                          4.15-4.4(br, 2H), 8.27(d, J=12.8Hz,                                           1H), 8.97(s, 1H)                                                                                 ##STR183##            __________________________________________________________________________

EXAMPLE 111 Ethyl6,7-difluoro-1-(1H-tetrazol-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.180)

A mixture of ethyl 2,4,5-trifluorobenzoylacetate (9.8 g), ethylorthoformate (10 ml) and acetic anhydride (17 ml) was stirred at 130° C.for 4 hours. After the solvent was removed in vacuo, a solution of5-amino-1H-tetrazole (3.4 g) in benzene (20 ml) and methanol (80 ml) wasadded to the residue. The mixture was stirred at 60° C. for 20 minutes.The solvent was removed in vacuo. After addition of hexane (100 ml) tothe residue, the precipitate was filtrated to obtain 7 g of a colorlesssolid. A solution of this solid (7.0 g) and potassium carbonate (5.5 g)in N,N-dimethylformamide (40 ml) was stirred for 1 hour at 100° C. Thesolution was removed in vacuo. 6N-HCl (30 ml) was added to the residueand stirred for 10 minutes. The precipitate was filtrated and washedwith water, ethanol and ether successively. The title compound No. 180was obtained as a yellow solid (4 g).

Melting point: 233-236.5° C. ¹ H-NMR(DMSO-d₆) δ; 1.29(t,J=7 Hz,3H),4.26(q,J=7 Hz,2H), 7.99(dd,J=12 Hz,6.3 Hz,1H), 8.15(dd,J=10.7 Hz,8.5Hz,1H), 8.90(s,1H)

EXAMPLE 1126,7-Difluoro-1-(1H-tetrazol-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.181)

Compound No.180 (2 g) obtained in Example 111 was dissolved in asolution of acetic acid (10 ml) and 6N-HCl (10 ml). The solution wasstirred at 100° C. for 1 hour, and the solvent was removed. Afteraddition of water (100 ml) to the residue, the precipitate was filtratedand washed with ethanol and ether. The title compound No. 181 wasobtained as a pale yellow solid (1.1 g).

Melting point: 246°-249° C. ¹ H-NMR(DMSO-d₆) δ; 8.14 (dd,J=12 Hz,6.4Hz,1H), 8.31(dd,J=10 Hz,9 Hz,1H), 9.13(s,1H)

EXAMPLE 113

Compounds Nos. 182-183 listed in Table 39 were synthesized in a similarmanner to Example 11, proceeding from the compound No.181 in Example112.

                                      TABLE 39                                    __________________________________________________________________________    Compound:                                                                      ##STR184##                                                                   Compound                                                                             Group                                                                  No.    R.sup.2                                                                         Y          Z Property                                                                           Melting Point (°C.)                                                              .sup.1 H-NMR        Solvent              __________________________________________________________________________    182    H                                                                                ##STR185##                                                                               ##STR186##                                                                     Colorless solid                                                                    Colored from 280, decomposed                                                            [DMSO-d.sub.6 ] δ; 3.27(s,                                              4H), 3.40(s, 4H), 7.64(d, J=6.4Hz,                                            1H), 8.0(d, J=13.3Hz, 1H), 9.02(s,                                            1H), 9.24(brs, 2H)                                                                                 ##STR187##          183    H                                                                                ##STR188##                                                                               ##STR189##                                                                     Yellow solid                                                                       Colored from 270, decomposed                                                            [DMSO-d.sub.6 ] δ; 1.95-2.2(m,                                          1H), 2.2-2.4(m, 1H), 3.45-4.05(m,                                             5H), 7.19(d, J=6.8Hz, 1H), 7.89(d,                                            J=14.1Hz, 1H), 8.15(brs, 3H),                                                 8.90(s, 1H)                                                                                        ##STR190##          __________________________________________________________________________

EXAMPLE 114 Ethyl2-(2,6-dichloro-5-fluoronicotinoyl)-3-(4-methyl-1,2,5-thiadiazol-3-ylamino)acrylate(Compound No.184)

A mixture of ethyl 2,6-dichloro-5-fluoronicotinoylacetate (14.9 g),ethyl orthoformate (13.3 ml) and acetic anhydride (15 ml) was stirred at130° C. for 3 hours. After the solvent was removed in vacuo, a solutionof 3-amino-4-methyl-1,2,5-thiadiazole hydrochloride (7.7 g) andtriethylamine (5.2 g) in chloroform (80 ml) was added to the residue.The mixture was stirred at room temperature for 1 hour. The solvent wasremoved in vacuo. The residue was purified by column chromatography onsilicagel (chloroform as an eluent). The title compound No. 184 wasobtained as a yellow oil (20 g).

¹ H-NMR(CDCl₃) δ; 0.98 and 1.18(t,J=7 Hz,3H), 2.60 and 2.64(s,3H),4.08-4.21(m,2H), 7.43 and 7.56(d,J=7 Hz,1H), 8.98 and 9.06(d,J=12.6Hz,1H)

EXAMPLE 115 Ethyl7-chloro-6-fluoro-1-(4-methyl-1,2,5-thiadiazol-3-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate(Compound No.185)

To a solution of compound No.184 (20 g) obtained in Example 114 intetrahydrofuran (500 ml), 2.04 g of sodium hydride(60% in oil) was addedat room temperature. Then the solution was stirred for 0.5 hour at 70°C. After addition of 5% citric acid solution to make the system acidic,tetrahydrofuran was removed. Extraction was carried out with chloroform(500 ml). The organic phase was dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography on silicagel(chloroform/ethyl acetate 10:1 as an eluent). The title compound No. 185was obtained as a colorless solid (15.1 g).

Melting point: 191.5°-192.5° C. ¹ H-NMR(CDCl₃) δ; 1.41(t,J=7 Hz,3H),2.42(s,3H), 4.41(q,J=7 Hz,2H), 8.50(d,J=7 Hz,1H), 8.65(s,1H)

EXAMPLE 1167-Chloro-6-fluoro-1-(4-methyl-1,2,5-thiadiazol-3-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (Compound No.186)

Compound No.185 (15.1 g) obtained in Example 115 was dissolved in aceticacid (180 ml) and c-HCl (80 ml). The solution was stirred for 1 hourwith heating under reflux. After cooling, water (200 ml) was addedthereto. The precipitate was filtrated and washed with water, ethanoland ether. The title compound No. 186 was obtained as pale yellowneedles (13.3 g).

Melting point: 247°-249° C. ¹ H-NMR(DMSO-d₆) δ; 2.35(s,3H), 8.78(d,J=7.7Hz,1H), 9.17(s,1H)

EXAMPLE 1177-(3-(S)-Aminopyrrolidin-1-yl)-6-fluoro-1-(4-methyl-1,2,5-thiadiazol-3-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid hydrochloride (Compound No.187)

A mixture of compound No.186 (12 g), triethylamine (7.1g) and3-(S)-aminopyrrolidine (4.47 g) in acetonitrile (240 ml) was stirred at80° C. for 180 minutes. After cooling, the precipitate was filtrated andwashed with ethanol, followed by adding to a mixture of 200 ml of 6N-HCland 150 ml of acetic acid and heating until dissolved. After the solventwas removed in vacuo, ethanol was added. The precipitate was collectedby filtration and washed with ethanol and ether. The title compound wasobtained as a pale yellow solid (15.6 g). A water/.ethanol (1:1)solution was used for reprecipitation to obtain the title compound No.187 in a colorless solid (9.8 g).

Melting point: 278° C. decomposed ¹ H-NMR(DMSO-d₆) δ; 1.95-2.30(br,2H),2.37(s,3H), 3.7-4.2(br,2H), 8.12(d,J=12.4 Hz,1H), 8.4(brs,3H),8.96(s,1H)

This compound can also be obtained as slightly yellow needles bycrystallizing from water. It decomposes at a temperature of 299° C. orhigher.

EXAMPLE 118

Compounds Nos. 188-193 listed in Tables 40 and 41 were synthesized in asimilar manner to Example 117.

                                      TABLE 40                                    __________________________________________________________________________    Compound:                                                                      ##STR191##                                                                   Compound                    Melting Point                                     No.   R.sup.2                                                                         Y          Z Property                                                                             (°C.)                                                                         .sup.1 H-NMR       Solvent                 __________________________________________________________________________    188   H                                                                                ##STR192##                                                                              N Pale yellow solid                                                                    Decomposed from 286                                                                  [DMSO-d.sub.6 ] δ; 2.34(s, 3H),                                         3.12(s, 4H) 3.74(s, 4H), 8.23(d,                                              J=12.8Hz, 1H), 9.04(s, 1H), 9.65(brs,                                         2H)                                                                                               ##STR193##             189   H                                                                                ##STR194##                                                                              N Colorless solid                                                                      Decomposed from 293                                                                  [DMSO-d.sub.6 ] δ; 1.03(d,                                              J=6Hz, 3H), 2.37(s, 3H), 2.45-2.7(brs,                                        1H), 3.2-4.2(m, 5H), 8.13(d, J=12.4Hz,                                        1H), 8.25(brs, 3H), 8.95(s,                                                                       ##STR195##             190   H                                                                                ##STR196##                                                                              N Colorless solid                                                                      191.5  [DMSO-d.sub.6 ] δ; 2.34(s, 3H),                                         3.5-4.6(m, 6H), 7.98(d, J=11.6Hz, 1H),                                        .70(s, 1H)         Et.sub.3 N CH.sub.3                                                           CN (no acid                                                                   treatment)              __________________________________________________________________________

                                      TABLE 41                                    __________________________________________________________________________    Compound                    Melting Point                                     No.   R.sup.2                                                                         Y            Z Property                                                                           (°C.)                                                                         .sup.1 H-NMR       Solvent                 __________________________________________________________________________    191   H                                                                                ##STR197##  N Colorless solid                                                                    237-239.5                                                                            [DMSO-d.sub.6 ] δ; :2.35(s, 3H),                                        .8-4.95(m, 4H), 8.15(d, J=11.6Hz, 1H),                                        .59(brs, 3H), 8.96(s,                                                                             ##STR198##             192   H                                                                                ##STR199##  N Pale yellow solid                                                                  214-218                                                                              [DMSO-d.sub.6 ] δ; 2.35(s, 3H),                                         2.7-3.15(m, 3H), 3.6-4.5(m, 4H),                                              7.99(d, J=11.1Hz, 1H), 8.82(s,                                                                   Et.sub.3 N CH.sub.3                                                           CN (no acid                                                                   treatment               193   H                                                                                ##STR200##  N Pale yellow solid                                                                  Decomposed from 278                                                                  [DMSO-d.sub.6 ] δ; 2.36(s, 3H),                                         4.9-5.2(m, 1H), 8.13(d, J=11.1Hz, 1H),                                        .97(s, 1H)         Et.sub.3 N CH.sub.3                                                           CN (no acid                                                                   treatment               __________________________________________________________________________

EXAMPLE 119 Benzyl6,7-difluoro-1-(1,2,4-triazol-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.194)

A mixture of benzyl 2,4,5-trifluorobenzoylacetate (1.5 g), ethylorthoformate (1.08 g) and acetic anhydride (2.24g) was stirred at 130°C. for 3 hours. After the excessive acetic anhydride and ethylorthoformate were removed in vacuo, a solution of 3-amino-1,2,4-triazole(0.41 g) in methanol (25 ml ) was added to the residue. The mixture wasstirred at room temperature for 3 days. The solvent was removed. Theresidue was purified with a silicagel column (chloroform/ethyl acetate10:1-5:1 as an eluent). The title compound was obtained as pale yellowneedles (1.10 g).

Melting point: 116°-124° C. ¹ H-NMR(DMSO-d₆) δ; 5.23(d,J=4.9 Hz,2H),7.22-7.41(m,5H), 7.58-7.70(m,1H), 7.74-7.88(m,1H), 8.80(s,1H),9.42(s,1H)

EXAMPLE 1206,7-Difluoro-1-(1,2,4-triazol-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.195) and6,7-difluoro-1-(N-benzyl-1,2,4-triazol-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.196)

To a solution of compound No.194 (1.02 g) in tetrahydrofuran (50 ml) wasadded a solution of Pd/C (300 mg) ethanol (50 ml), then stirred under H2gas atmosphere for 1 day. After removing the catalyst with a membranefilter, the filtrate was evaporated. The residue was purified with asilicagel column (chloroform/ethyl acetate 1:1 as an eluent). Acolorless solid No. 195 was first obtained (53 mg), and next, acolorless solid of N-benzyl, No. 196 was obtained (95 mg).

The melting point and the ¹ H-NMR data of the compound 195 are asfollows:

Melting point: 170°-177° C. ¹ H-NMR(DMSO-d₆) δ; 7.79-7.98(m,2H),8.79(s,1H), 9.38(s,1H)

The melting point and the ¹ H-NMR data of the compound 196 are asfollows:

Melting point: 244-258° C. ¹ H-NMR (DMSO-d₆) δ; 4.9 and 5.17(d,J=12.7Hz,2H), 6.52(s,1H), 7.16-7.23(m,2H), 7.27-7.33(m,3H), 7.42-7.54(m,2H),7.68 and 7.71(s,1H)

EXAMPLE 1217-(3-(S)-Aminopyrrolidin-1-yl)-6-fluoro-1-(1,2,4-triazol-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.197)

A mixture of compound No.194 (50 mg) was dissolved in acetonitrile (5ml), to which triethylamine (21 mg) and 3-(S)-aminopyrrolidine (21 mg)were added and stirred at 80° C. for 30 minutes. The precipitate wasfiltrated and washed with ethanol. The title compound No. 197 wasobtained as a yellow solid (46 mg).

Melting point: 250°-260° C., colored from approx. 245° C. ¹H-NMR(DMSO-d₆) δ; 1.65-1.82(m,1H), 1.98-2.12(m,1H), 3.51-3.77(m,4H),6.60(d,J=7.8 Hz,1H ), 8.88(d,J=16.1 Hz,1H), 8.94(s,1H), 9.22(s,1H)

EXAMPLE 122 Ethyl2-(2,6-dichloro-5-fluoronicotinoyl)-3-(1-methyl-1,2,4-triazol-5-ylamino)acrylate(Compound No.198)

A mixture of ethyl 2,6-dichloro-5-fluoronicotinoylacetate (3.00 g),ethyl orthoformate (2.38 g) and acetic anhydride (3.85 g) was stirred at130° C. for 2 hours. After the excessive acetic anhydride and ethylorthoformate were removed in vacuo, the residue was dissolved inchloroform (50 ml). A solution of 5-amino-1-methyl-1,2,4-triazole (1.05g) in chloroform (30 ml) was added thereto. The mixture was stirred atroom temperature overnight. The solvent was removed. The residue waspurified with a silicagel column (chloroform/ethyl acetate 5:1 as aneluent). The title compound No. 198 was obtained as a yellow solid (2.34g).

Melting point: 102°-103° C. ¹ H-NMR(CDCl₃) δ; 1.20 and 1.26(t,J=7Hz,3H), 3.86 and 3.91(s,3H), 4.06-4.23(m,2H), 7.42 and 7.56(d,J=7Hz,1H), 7.72 and 7.76(s,1H), 8.85 and 8.97(d,J=12.2 Hz,1H)

EXAMPLE 123 Ethyl7-chloro-6-fluoro-1-(1-methyl-1,2,4-triazol-5-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate(Compound No.199)

A solution of compound No.198 (1.00 g) and potassium carbonate (0.39 g)in dimethylformamide (20 ml) was stirred for 30 minutes at 90° C. Thesolvent was removed and a 5% citric acid solution (50 ml) and chloroform(50 ml) were added thereto. The organic phase was dehydrated withGlauber's salt, followed by evaporation of solvent. The residue wassuspended in a small amount of ethyl acetate for filtration. The titlecompound No. 199 was obtained as a colorless solid (0.79 g).

Melting point: 256°-263° C. ¹ H-NMR(CDCl₃) δ; 1.39(t,J=7 Hz,3H),3.80(s,3H), 4.40(q,J=7 Hz,2H), 8.04(s,1H), 8.48(d,J=7.3 Hz,1H),8.62(s,1H)

EXAMPLE 1247-Chloro-6-fluoro-1-(1-methyl-1,2,4-triazol-5-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (Compound No.200)

Compound No.199 (0.1 g) was dissolved in acetic acid (10 ml) and 6N-HCl(3 ml). The solution was stirred at 110° C. for 1 hour. Afterevaporation of the solvent, the residue was suspended in diethyletherfor filtration. The title compound No. 200 was obtained as a colorlesssolid (80 mg).

Melting point: 238-242° C. ¹ H-NMR(DMSO-d₆) δ; 3.71(s,3H), 8.22(s,1H),8.75(d,J=7.8 Hz,1H), 9.06(s,1H)

EXAMPLE 1257-(3-(S)-Aminopyrrolidin-1-yl)-6-fluoro-1-(1-methyl-1,2,4-triazol-5-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid hydrochloride (Compound No.201)

A mixture of compound No.200 (50 mg), triethylamine (40 mg) and3-(S)-aminopyrrolidine (24 mg) in acetonitrile (5 ml) was stirred at 80°C. for 60 minutes. The precipitate was filtrated and washed withethanol, and was dissolved in 6N-HCl to obtain a hydrochloride. Thesolvent was removed and suspended in diethylether for filtration. Thetitle compound No. 201 was obtained as a pale brown solid (47 mg).

Melting point: Colored from approx. 240° C., 265-275° C. decomposed ¹H-NMR(DMSO-d₆) δ; 2.13(brs,1H), 2.20(brs,1H), 3.72(s,3H), 8.14(d,J=12.2Hz,1H), 8.20(s,1H), 8.35(brs,3H), 8.88(s,1H)

EXAMPLE 126

Compounds Nos. 202 and 203 listed in Table 42 were synthesized in asimilar manner to Example 125.

                                      TABLE 42                                    __________________________________________________________________________    Compound:                                                                      ##STR201##                                                                   Compound                    Melting point                                     No.   R.sup.2                                                                         Y          Z Property                                                                             (°C.)                                                                          .sup.1 H-NMR      Solvent                 __________________________________________________________________________    202   H                                                                                ##STR202##                                                                              N Pale yellow solid                                                                    270 or more                                                                           [DMSO-d.sub.6 ] δ; 1.06(d,                                              J=6.4Hz, 3H), 2.40-2.70(brs, 1H),                                             3.72(s, 3H), 8.13(d, J=12.7Hz, 1H),                                           8.19(s, 1H), 8.86(s,                                                                             ##STR203##             203   H                                                                                ##STR204##                                                                              N Pale yellow solid                                                                    270 or more                                                                           [DMSO-d.sub.6 ] δ; 3.17(brs,                                            4H), 3.70(s, 4H), 3.72(s, 3H),                                                8.21(s, 1H), 8.27(d, J=13.2Hz, 1H),                                           8.97(s, 1H)       "                       __________________________________________________________________________

EXAMPLE 127 Ethyl2-(2,4,5-trifluorobenzoyl)-3-(1-methyl-1,2,4-triazol-5-ylamino)acrylate(Compound No.204)

A mixture of ethyl 2,4,5-trifluorobenzoylacetate (1.50 g), ethylorthoformate (2.24 g) and acetic anhydride (1.09 g) was stirred at 130°C. for 3 hours. After the excessive acetic anhydride and ethylorthoformate were removed in vacuo, a solution of5-amino-1-methyl-1,2,4-triazole (0.48 g) in benzene (30 ml) and methanol(15 ml) was added to the residue. The mixture was stirred at roomtemperature overnight. The solvent was removed. The residue was purifiedwith a silicagel column (chloroform as an eluent). The title compoundNo. 204 was obtained as a yellow oil (0.43 g).

¹ H-NMR(CDCl₃) δ; 1.05 and 1.21(t,J=7 Hz,3H), 3.83 and 3.88(s,3H),4.10-4.22(m,2H), 6.87-6.97(m,1H), 7.29-7.37 and 7.47-7.37(m,1H), 7.68and 7.72(s,1H), 8.57 and 8.84(d,J=12 Hz,1H)

EXAMPLE 128 Ethyl6,7-difluoro-1-(1-methyl-1,2,4-triazol-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.205)

A solution of compound No.204 (347 mg) and potassium carbonate (148 mg)in dimethylformamide (8 ml) was stirred for 30 minutes at 90° C. Thesolution was removed. An aqueous 5% citric acid (25 ml) and chloroform(25 ml) were used for separation. The organic phase was dried over Na₂SO₄, followed by evaporation. A small amount of ethyl acetate was addedto the residue and the precipitate was filtrated. The title compound No.205 was obtained as a colorless solid (0.235 g).

Melting point: 230-231° C. ¹ H-NMR(CDCl₃) δ; 1.40(t,J=7 Hz,3H),3.81(s,3H), 4.40(q,J=7 Hz,2H), 6.67(dd,J=6 Hz,J=10 Hz,1H), 8.13(s,1H),8.29(dd,J=8.3 Hz,J=9.8 Hz,1H), 8.39(s,1H)

EXAMPLE 1296,7-Difluoro-1-(1-methyl-1,2,4-triazol-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.206)

Compound No.205 (0.2 g) was dissolved in acetic acid (10 ml) and 6N-HCl(3 ml). The solution was stirred at 110° C. for 1 hour. Afterevaporation of the solvent, the residue was suspended in diethyletherfor filtration. The title compound No. 206 was obtained as colorlesssolid (166 mg).

Melting point: 254°-264° C. ¹ H-NMR(DMSO-d₆) δ; 3.76(S,3H) ,7.37(dd,J=6.3 Hz,J=11.2 Hz,1H), 8.28(S,1H), 8.34(dd,J=8.3 Hz,J=10.3Hz,1H), 9.16(s,1H)

EXAMPLE 1307-(3-(S)-Aminopyrrolidin-1-yl)-6-fluoro-1-(1-methyl-1,2,4-triazol-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride (Compound No.207)

A mixture of compound No.206 (50 mg), triethylamine (39 mg) and3-(S)-aminopyrrolidine (22 mg) in acetonitrile (5 ml) was stirred at 80°C. for 60 minutes. The precipitate was filtrated and washed withethanol, then dissolved in 6N-HCl to obtain a hydrochloride. The solventwas removed and suspended in diethylether for filtration. The titlecompound No. 207 was obtained as a pale yellow solid (59 mg).

Melting point: Colored from approx. 257° C., 262-266° C. decomposed ¹H-NMR(DMSO-d₆) δ; 2.01-2.16(brs,1H), 2.16-2.28(brs,1H),3.40-3.52(brs,1H), 3.52-3.67(brs,2H), 3.75(s,3H), 3.82-3.93(brs,1H),5.70(d,J=7.3 Hz,1H), 7.93 (d,J=14.2 Hz,1H), 8.32(s,1H), 9.00(s,1H)

EXAMPLE 131 Ethyl2-(2,4,5-trifluorobenzoyl)-3-(1,2,3-triazol-4-ylamino)acrylate (CompoundNo.208)

A mixture of ethyl 2,4,5-trifluorobenzoylacetate (2.00 g), ethylorthoformate (1.81 g) and acetic anhydride (3.73 g) was stirred at 130°C. for 3 hours. The excessive acetic acid and ethyl orthoformate wereremoved in vacuo, and the residue was dissolved in benzene (30 ml), towhich a solution of 4-amino-1,2,3-triazole (0.68 g) in methanol (20 ml)was added. The mixture was stirred at room temperature overnight. Thesolvent was removed. The residue was purified with a silicagel column(chloroform/ethyl acetate 10:1 as an eluent). The title compound No. 208was obtained as a yellow solid (1.93 g).

Melting point: 157°-159° C. ¹ H-NMR(CDCl₃) δ; 1.02 and 1.14(t,J=7Hz,3H), 4.04-4.20(m,2H), 6.84-6.97(m,1H), 7.26-7.36 and 7.42-7.56(m,1H), 7.57 and 7.61(s,1H), 8.52 and 8.70(d,J=13.2 Hz,1H)

EXAMPLE 132 Ethyl6,7-difluoro-1-(1,2,3-triazol-4-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.209)

A solution of compound No.208 (300 mg) and potassium carbonate (124 mg)in dimethylformamide (6 ml) was stirred for 30 minutes at 90° C. Thesolvent was removed. The residue was suspended in water for filtration.The title compound No. 209 was obtained as a pale yellow solid (221 mg).

Melting point: 298° C. ¹ H-NMR(DMSO-d₆) δ; 1.27(t,J=7 Hz,3H), 4.23(B,J=7Hz,2H), 7.36((dd,J=6.8 Hz, J=11.7 Hz,1H), 8.15(dd,J=8.8 Hz,J=10.7Hz,1H), 8.51(s,1H), 8.59(s,1H)

EXAMPLE 1336,7-Difluoro-1-(1,2,3-triazol-4-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.210)

Compound No.209 (0.1 g) was dissolved in tetrahydrofuran (10 ml) and6N-HCl (3 ml). The solution was refluxed with heating for 1 hour. Afterevaporation of the solvent, the residue was suspended in diethyletherfor filtration. The title compound No. 210 was obtained as a pale yellowsolid (82 mg).

Melting point: 215-224° C. ¹ H-NMR(DMSO-d₆) δ; 7.58(dd,J=6.8 Hz,J=11.7Hz,1H), 8.34(dd,J=8.3 Hz, J=10.3 Hz,1H), 8.45-8.59(brs,1H), 8.88(s,1H)

EXAMPLE 1347-(3-(S)-Aminopyrrolidin-1-yl)-6-fluoro-1-(1,2,3-triazol-4-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.211)

A mixture of compound No.210 (50 mg), triethylamine (38 mg) and3-(S)-aminopyrrolidine (27 mg) in acetonitrile (5 ml) was stirred at 80°C. for 30 minutes. The precipitate was filtrated and washed withethanol. The title compound No. 211 was obtained as a pale brown solid(47 mg).

Melting point: 300° C. ¹ H-NMR(DMSO-d₆) δ; 1.57-1.69(brs,1H),1.69-1.83(brs,1H), 6.54(d,J=7.8 Hz,1H), 7.73(s,1H), 7.83(d,J=14.2Hz,1H), 8.51(s,1H)

EXAMPLE 135 Ethyl2-(2,6-dichloro-5-fluoronicotinoyl)-3-(1-methyl-1,2,3-triazol-5-ylamino)acrylate(Compound No.212)

A mixture of ethyl 2,6-dichloro-5-fluoronicotinoylacetate (2.80 g),ethyl orthoformate (2.22 g) and acetic anhydride (3.57 g) was stirred at130° C. for 1.5 hours. After the excessive acetic acid and ethylorthoformate were removed, the residue was dissolved in chloroform (50ml). A solution of 5-amino-1-methyl-1,2,3-triazole (98 ml) in methanol(60 ml) was added thereto. The mixture was stirred at room temperaturefor 0.5 hour. The solvent was removed and then purified through asilicagel column (chloroform/methanol 40:1 as an eluent). The solidifiedsubstance was suspended in n-hexane for filtration. The title compoundNo. 212 was obtained as a colorless solid (2.94 g).

Melting point: 187-189° C. ¹ H-NMR(CDCl₃) δ; 0.96 and 1.12(t,J=7 Hz,3H),4.05-4.25(m,2H), 4.10(s,3H), 7.43(d,J=6.8 Hz), 7.74(s,1H), 8.32 and8.36(s,1H)

EXAMPLE 136 Ethyl6-fluoro-7-chloro-1-(1-methyl-1,2,3-triazol-5-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate(Compound No.213)

A solution of compound No.212 (300 mg) and potassium carbonate (107 mg)in dimethylformamide (6 ml) was stirred for 30 minutes at 90° C. Thesolvent was removed. An aqueous 5% citric acid (25 ml) and chloroform(100 ml) were used for separation. The organic phase was dried over Na₂SO₄ and the solvent was removed. The residue was suspended indiethylether for filtration. The title compound No. 213 was obtained asa colorless solid (249 mg).

Melting point: 251° C. decomposed ¹ H-NMR(CDCl₃) δ; 1.40(t,J=7 Hz,3H),3.95(s,3H), 4.41(q,J=7 Hz,2H), 7.89(s,1H), 8.46(s,1H), 8.49(d,J=6.8Hz,1H)

EXAMPLE 1376-Fluoro-7-chloro-1-(1-methyl-1,2,3-triazol-5-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (Compound No.214)

Compound No.213 (1.51 g) was dissolved in acetic acid (70 ml) and 6N-HCl(20 ml). The solution was stirred at 110° C. for 1 hour. Afterevaporation of the solvent, the residue was suspended in diethyletherfor filtration to obtain the title compound No. 214 as a pale yellowsolid (1.33 g).

Melting point: 240°-245° C. ¹ H-NMR (DMSO-d₆) δ; 3.87(s,3H), 8.12(s,1H),8.78(d,J=8.3 Hz,1H), 9.00(s,1H)

EXAMPLE 1387-(3-(S)-Aminopyrrolidin-1-yl)-6-fluoro-1-(1-methyl-1,2,3-triazol-5-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid hydrochloride (Compound No.215)

A mixture of compound No.214 (50 mg), triethylamine (36 mg ) and3-(S)-aminopyrrolidine (19 mg) in acetonitrile (5 ml) was stirred at 80°C. for 60 minutes. After the precipitate was collected by filtration, itwas washed with ethanol, then dissolved in 6N-HCl to obtain ahydrochloride. After the solvent was removed, the residue was suspendedin diethylether for filtration. The title compound No. 215 was obtainedas a pale orange solid (37 mg).

Melting point: 269° C. decomposed ¹ H-NMR(DMSO-d₆) δ; 1.92-2.13(brs,1H),2.13-2.30(brs,1H), 3.88(s,3H), 8.09(s,1H), 8.14(d,J=12.2 Hz,1H),8.28(brs,3H), 8.78(s,1H)

EXAMPLE 139

Compound Nos. 216-217 listed in Table 43 were synthesized in a similarmanner to Example 138.

                                      TABLE 43                                    __________________________________________________________________________    Compound:                                                                      ##STR205##                                                                   Compound                     Melting point                                    No.   R.sup.2                                                                         Y          Z  Property                                                                             (°C.)                                                                          .sup.1 H-NMR     Solvent                 __________________________________________________________________________    216   H                                                                                ##STR206##                                                                              N  Pale yellow solid                                                                    Decomposed from 255                                                                   [DMSO-d.sub.6 ] δ; 1.05(d,                                              J=6Hz, 3H), 2.42-2.67(brs, 1H),                                               3.88(s, 3H), 8.09(s, 1H), 8.14(d,                                             J=12.7Hz, 1H), 8.21(brs, 3H),                                                 8.78(s, 1H)      Et.sub.3 N/CH.sub.3                                                           CN                      217   H                                                                                ##STR207##                                                                              N  Pale yellow solid                                                                    Decomposed from 275                                                                   [DMSO-d.sub.6 ] δ; 3.31(brs,                                            4H), 3.90(brs, 4H), 3.93(s, 3H),                                              8.07-8.14(brs, 1H), 8.17(d,                                                   J=13.2Hz, 1H), 8.88(s,                                                                         "H)                     __________________________________________________________________________

EXAMPLE 140 Ethyl2-(2,6-dichloro-5-fluoronicotinoyl)-3-(1-methyltetrazol-5-ylamino)acrylate(Compound No.218)

A mixture of ethyl 2,6-dichloro-5-fluoronicotinoylacetate (1.04 g),ethyl orthoformate (1.12 g) and acetic anhydride (1.80 g) was stirred at130° C. for 2 hours. The excessive acetic anhydride and ethylorthoformate were removed, and dissolved in chloroform (30 ml), to whicha solution of 5-amino-1-methyltetrazole in methanol was added. Themixture was stirred at room temperature for 3 days. The solvent wasremoved. The residue was purified through a silicagel column(chloroform/ethyl acetate 10:1 as an eluent). The title compound No. 218was obtained as a red-brown oil (516 mg).

¹ H-NMR(CDCl₃) δ; 0.99 and 1.22(t,7 Hz,3H), 4.01-4.24(m,2H), 4.05 and4.10(s,3H), 7.34 and 7.44(d,J=7.0 Hz,1H), 8.81 and 8.99(d,J=12 Hz,1H)

EXAMPLE 141 Ethyl6-fluoro-7-chloro-1-(1-methyltetrazol-5-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate(Compound No.219)

To a solution of compound No.218 (0.08 g) in tetrahydrofuran (8 ml), 11mg of sodium hydride was added. Then the solution was stirred for 2 daysat room temperature. After addition of 5% citric acid solution forneutralization, the solvent was removed. A citric acid solution andchloroform were used for separation. The organic phase was dried overNa₂ SO₄ and the solvent was removed. The residue was purified through asilicagel column (chloroform:ethyl acetate=1:1). The title compound No.219 was obtained as a pale yellow solid (21 mg).

Melting point: 210°-215° C. ¹ H-NMR(CDCl₃) δ; 1.40(t,J=7 Hz,3H),4.06(s,3H), 4.41(q,J=7 Hz,2H), 8. 51(d,J=6.8 Hz,1H), 8.65(s,1H)

EXAMPLE 1426-Fluoro-7-chloro-1-(1-methyltetrazol-5-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (Compound No.220)

Compound No.219 (123 mg) was dissolved in acetic acid (5 ml) and 6N-HCl(5 ml). The solution was stirred at 110° C. for 2 hours. Afterevaporation of the solvent, the residue was submitted to a constantboiling with toluene. The residue was suspended in diethylether forfiltration. The title compound No. 220 was obtained as a pale brownsolid (101 mg).

Melting point: 213°-220° C. ¹ H-NMR(DMSO-d₆) δ; 3.97(s,1H), 8.77(d,J=7.8Hz,1H), 9.09(s,1H)

EXAMPLE 1437-(3-(S)-Aminopyrrolidin-1-yl)-6-fluoro-1-(1-methyltetrazol-5-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid hydrochloride (Compound No. 221 )

A mixture of compound No.220 (45 mg), triethylamine (37 mg) and3-(S)-aminopyrrolidine (13 mg) in acetonitrile (5 ml) was stirred atroom temperature for 5 minutes. The precipitate was filtrated, washedwith ethanol, and dissolved in 6N-HCl to obtain a hydrochloride. Afterthe solvent was removed, the residue was suspended in diethylether forfiltration. The title compound No. 221 was obtained as a pale yellowsolid (38 mg).

Melting point: 258° C. decomposed ¹ H-NMR(DMSO-d₆) δ; 1.96-2.15(brs,1H),215-2.31(brs,1H), 3.87(brs, 2H), 3.94(s,1H), 3.99(s,3H), 8.15(d,J=12.7Hz,1H), 8.30(brs,3H), 8.95(s,1H)

EXAMPLE 144

Compound No. 222 listed in Table 44 was synthesized in a similar mannerto Example 143.

                                      TABLE 44                                    __________________________________________________________________________    Compound:                                                                      ##STR208##                                                                   Compound                     Melting point                                    No.   R.sup.2                                                                          Y          Z  Property                                                                            (°C.)                                                                          .sup.1 H-NMR     Solvent                 __________________________________________________________________________    222   H                                                                                 ##STR209##                                                                              N  Pale brown solid                                                                    Decomposed from 248                                                                   [DMSO-d.sub.6 ] δ;                                                      2.42-2.65(br, 1H), 3.76(brs, 2H),                                             3.94(s, 1H), 3.99(s, 3H), 8.15(d,                                             J=12.7Hz, 1H), 8.29(brs, 3H),                                                 8.94(s, 1H)                                                                                     ##STR210##             __________________________________________________________________________

EXAMPLE 145 Ethyl2-(2-methyl-3,4,6-trifluorobenzoyl)-3-(4-methyl-1,2,5-oxadiazol-3-ylamino)acrylate(Compound No.223)

A mixture of ethyl 2-methyl-3,4,6-trifluorobenzoylacetate (2.6 g), ethylorthoformate (2.5 ml) and acetic anhydride (2.8 ml) was stirred at 130°C. for 2 hours. After the solvent was removed in vacuo, a solution of3-amino-4-methyl-1,2,5-oxadiazole (0.99 g) in chloroform(20 ml) wasadded to the residue. The mixture was stirred at room temperature for 24hours. The solvent was removed. The residue was purified bychromatography on silicagel (chloroform as an eluent). The titlecompound No. 223 was obtained as a yellow oil (3.4 g).

¹ H-NMR(CDCl₃) δ; 1.01 and 1.16(t,J=7 Hz,3H), 2.22 and 2.28(d,J=2.2Hz,3H), 2.46 and 2.51(s,3H), 4.05-4.2(m,2H), 6.7-6.9(m,1H), 8.62 and8.79(d,J=12.6 Hz,1H)

EXAMPLE 146 Ethyl5-methyl-6,7-difluoro-1-(4-methyl-1,2,5-oxadiazol-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.224)

To a solution of compound No.223 (3.4 g) in tetrahydrofuran (50 ml),0.37 g of sodium hydride (60% in oil) was added. Then the solution wasstirred for 7 hours at 70° C. After the solvent was removed and a 5%citric acid solution (10 ml) was added thereto, extraction was carriedout with chloroform (100 ml), followed by drying over MgSO₄ andevaporation. To the residue was added isopropylether, and theprecipitate was filtrated. The title compound No. 224 was obtained as ayellow solid (1.68 g).

Melting point: 173.5°-174.0° C. ¹ H-NMR(DMSO-d₃) δ; 1.39(t,J=7 Hz,3H),2.35(s,3H), 2.91(d,J=2.6 Hz,3H), 4.39(q,J=7 Hz,2H), 6.49(dd,J=6 Hz,J=11Hz,1H), 8.25(s,1H)

EXAMPLE 1475-Methyl-6,7-difluoro-1-(4-methyl-1,2,5-oxadiazol-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.225)

Compound No.224 (1.68 g) was dissolved in acetic acid (20 ml) and 6N-HCl(6 ml). The solution was stirred at 110° C. for 50 minutes. Aftercooling, ice (50 ml) was added thereto, and the precipitate wasfiltrated, followed by washing with water, ethanol and isopropyl ether.The title compound No. 225 was obtained as a yellow solid (1.43 g).

Melting point: 199.5°-202° C. ¹ H-NMR(DMSO-d₆) δ; 2.29(s,3H),2.85(d,J=2.5 Hz,3H), 7.51(dd,J=6.8 Hz, J=11.1 Hz,1H), 9.08(s,1H)

EXAMPLE 148

Compounds Nos. 226-229 listed in Table 45 were synthesized in a similarmanner to Example 117, proceeding from the compound No.225.

                                      TABLE 45                                    __________________________________________________________________________    Compound:                                                                      ##STR211##                                                                   Compound                     Melting point                                    No.   R.sup.2                                                                          Y          Z Property                                                                             (°C.)                                                                         .sup.1 H-NMR       Solvent                __________________________________________________________________________    226   Me                                                                                ##STR212##                                                                               ##STR213##                                                                     Pale yellow solid                                                                    Decomposed from 266                                                                  [DMSO-d.sub.6 ] δ; 2.0-2.4(m,                                           2H), 2.33(s, 3H), 2.77(s, 3H),                                                3.4-3.9(m, 5H), 5.73(d, J=7.7Hz, 1H),                                         .36(brs, 3H), 8.89(s,                                                                             ##STR214##            227   Me                                                                                ##STR215##                                                                               ##STR216##                                                                     Pale yellow solid                                                                    241-245                                                                              [DMSO-d.sub.6 ] δ; 1.08(d,                                              J=6.5Hz, 3H), 2.33(s, 3H), 2.4-2.6(m,                                         1H), 2.76(s, 3H), 3.5-4.9(m, 5H),                                             5.70(d, J=6Hz, 1H), 8.37(brs, 3H)                                             8.89(s, 1H)        "                      228   Me                                                                                ##STR217##                                                                               ##STR218##                                                                     Colorless solid                                                                      Decomposed from 273                                                                  [DMSO-d.sub.6 ] δ; 2.31(s, 3H),                                         2.79(s, 3H), 3.22(s, 4H), 3.4(s, 4H),                                         .38(d, J=7.7Hz, 1H), 8.98(s, 1H),                                             9.42(brs, 2H)      "                      229   Me                                                                                ##STR219##                                                                               ##STR220##                                                                     Colorless solid                                                                      241-242.5                                                                            [DMSO-d.sub.6 ] δ; 2.29(s, 3H),                                         .69(d, J=3Hz, 3H), 3.6-3.85(m, 3H),                                           4.24(brs, 2H), 5.53(d, J=8.1Hz, 1H),                                          8.82(s, 1H)         Et.sub.3 N                                                                   CH.sub.3 CN            __________________________________________________________________________

EXAMPLE 149 Ethyl2-(2,3,4,5-tetrafluorobenzoyl)-3-(4-methyl-1,2,5-oxadiazol-3-ylamino)acrylate(Compound No.230)

A mixture of ethyl 2,3,4,5-tetrafluorobenzoylacetate (1.06 g), ethylorthoformate (1.2 ml) and acetic anhydride (1.3 ml) was stirred at 130°C. for 5 hours. After the solvent was removed in vacuo, a solution of3-amino-4-methyl-1,2,5-oxadiazole (0.4 g) and triethylamine (0.4 g) inchloroform (10 ml) was added to the residue. The mixture was stirred atroom temperature for 1 hour. The solvent was removed. The residuewas-purified by chromatography on silicagel (chloroform/ethyl acetate10:1 as an eluent). The title compound No. 230 was obtained as a paleyellow solid (1.17 g).

Melting point: 88°-92° C. ¹ H-NMR(CDCl₃) δ; 1.07 and 1.24(t,J=7 Hz,3H),2.46 and 2.49(s,3H), 4.1-4.3(m,2H), 7.1-7.4(m,1H), 8.47 and 8.73(d,J=12.6 Hz,1H)

EXAMPLE 150 Ethyl6,7,8-trifluoro-1-(4-methyl-1,2,5-oxadiazol-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.231)

To a solution of compound No.230 (1.2 g) in tetrahydrofuran (50 ml),0.128 g of sodium hydride (60% in oil) was added. Then the solution wasstirred for 1 hour at 50° C. After addition of 5% citric acid solution(10 ml), tetrahydrofuran was removed in vacuo. The precipitate wasfiltrated and washed with water, ethanol and ether. The title compoundNo. 231 was obtained as a colorless solid (0.92 g).

Melting point: 201°-202° C. ¹ H-NMR(CDCl₃) δ; 1.4(t,J=7 Hz,3H),2.4(s,3H), 4.4(q,J=7 Hz,2H), 8.15-8.25(m,1H), 8.29(s,1H)

EXAMPLE 1516,7,8-Trifluoro-1-(4-methyl-1,2,5-oxadiazol-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacids(Compound No.232)

Compound No.231 (0.8 g) was dissolved in acetic acid (10 ml) and c-HCl(4 ml). The solution was stirred at 110° C. for 2 hours. After cooling,50 ml of water was added, and the precipitate was filtrated and washedwith water, ethanol and ether. The title compound No. 232 was obtainedas a colorless solid (0.6 g).

Melting point: 204.5°-205° C. ¹ H-NMR(DMSO-d₆) δ; 2.4(s,3H),8.2-8.3(m,1H), 9.08(s,1H)

EXAMPLE 1526,8-Difluoro-7-(3-(S)-aminopyrrolidin-1-yl)-1-(4-methyl-1,2,5-oxadiazol-3-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No.233)

A mixture of compound No.232 (100 mg),triethylamine 63 mg) and3-(S)-aminopyrrolidine(40 mg) in acetonitrile (3 ml) was stirred at 80°C. for 3 minutes. After cooling, the precipitate was filtrated. Thetitle compound No. 233 was obtained as a yellow solid (60 mg).

Melting point: 169°-170° C. ¹ H-NMR(DMSO-d₆ +CF₃ COO-d) δ; 1.99 and2.17(brs,2H), 2.37(s,3H), 3.87(brs,3H), 7.86(d,J=13.7 Hz,1H),8.11(brs,3H), 8.92(s,1H)

EXAMPLE 153

Compounds Nos. 234-239 listed in Tables 46 and 47 were synthesized in asimilar manner to Example 4, proceeding from the compound No.3.

EXAMPLE 154

Compounds Nos. 240-243 listed in Table 48 were prepared in a similarmanner to Example 11, proceeding from the compound No.159.

EXAMPLE 155

Compounds Nos. 244 and 245 listed in Table 49 were prepared in a similarmanner to Example 41, proceeding from the compound No.79.

                                      TABLE 46                                    __________________________________________________________________________    Compound:                                                                      ##STR221##                                                                   Compound                      Melting point                                   No.   R.sup.2                                                                          Y          Z  Property                                                                             (°C.)                                                                          .sup.1 H-NMR       Solvent              __________________________________________________________________________    234   H                                                                                 ##STR222##                                                                              N  Dim yellow solid                                                                     Decomposed from 251                                                                   [DMSO-d.sub.6 ] δ;                                                      3.05-4.2(m, 5H), 5.29 5.48(brs,                                               1H), 8.17(d, J=12.4Hz, 1H), 9.01(s,                                           1H), 9.38(s, 1H)   Et.sub.3 N                                                                    CH.sub.3 CN          235   H                                                                                 ##STR223##                                                                              N   Pale yellow solid                                                                   244-246 [DMSO-d.sub.6 ] δ;                                                      2.45-2.55(m, 4H), 3.9-4.0(m, 4H),                                             8.21(d, J=13.2Hz, 1H), 9.02(s, 1H),                                           9.31(s, 1H)        Et.sub.3 N                                                                    CH.sub.3 CN          236   H                                                                                 ##STR224##                                                                              N  Brown solid                                                                          Decomposed from 172                                                                   [DMSO-d.sub.6 ] δ; 2.98(s,                                              2H), 3.74(brs, 1H), 4.48(s, 1H),                                              5.9-6.2(m, 1H), 7.96(d, J=12.2Hz,                                             1H), 8.76(s, 1H), 9.49(s,                                                                        Et.sub.3 N                                                                    CH.sub.3             __________________________________________________________________________                                                             CN               

                                      TABLE 47                                    __________________________________________________________________________    Compound                       Melting point                                  No.   R.sup.2                                                                         Y             Z Property                                                                             (°C.)                                                                         .sup.1 H-NMR      Solvent               __________________________________________________________________________    237   H                                                                                ##STR225##   N Yellow solid                                                                         Decomposed from 280                                                                  [DMSO-d.sub.6 +         ] δ;                                            2.9-3.2(m, 3H), 3.7-4.4(m, 4H),                                               8.04(d, J=11.1Hz, 1H), 8.99(s, 1H),                                           .31(s, 1H)        Et.sub.3 N                                                                    CH.sub.3 CN           238   H                                                                                ##STR226##   N Pale yellow solid                                                                    217-220                                                                              [DMSO-d.sub.6 ] δ; 2.20(s,                                              6H), 2.4-2.7(m, 2H), 2.97(brs, 1H),                                           .4-4.6(m, 4H), 8.0(d, J=11.1Hz,                                               1H), 8.97(s, 1H), 9.31(s,                                                                       Et.sub.3 N                                                                    CH.sub.3 CN           239   H                                                                                ##STR227##   N Red solid                                                                            251-254                                                                              [CDCl.sub.3 ] δ; 1.3(s, 9H),                                            5.51(brs, 1H), 8.04(d, J=10.7Hz,                                              1H), 8.86(s, 1H), 8.89(s,                                                                       Et.sub.3 N                                                                    CH.sub.3 CN           __________________________________________________________________________

                                      TABLE 48                                    __________________________________________________________________________    Compound:                                                                      ##STR228##                                                                   Com-                          Melting                                         pound                         point                                           No. R.sup.2                                                                          Y             Z Property                                                                             (°C.)                                                                        .sup.1 H-NMR       Solvent                __________________________________________________________________________    240 Me                                                                                ##STR229##                                                                                  ##STR230##                                                                     Yellow solid                                                                         257-259                                                                             [DMSO-d.sub.6 ] δ; 2.7(s, 3H),                                          3.67(brs, 2H), 3.8(brs, 1H),                                                  4.21(brs, 2H), 5.79(d, J=6.8Hz, 1H),                                          8.81(s, 1H), 9.22(s,                                                                              ##STR231##            241 Me                                                                                ##STR232##                                                                                  ##STR233##                                                                     Colorless solid                                                                      242-244.5                                                                           [DMSO-d.sub.6 ] δ; 2.71(s, 6H),                                         .75(d, J=2.5Hz, 3H), 4.1-4.5(m, 5H),                                          5.98(d, J=7.7Hz, 1H), 8.86(s, 1H),                                            9.25(s, 1H)        "                      242 Me                                                                                ##STR234##                                                                                  ##STR235##                                                                     Pale yellow solid                                                                    De- composed from 231                                                               [DMSO-d.sub.6 ] δ; 2.7(s, 3H),                                          2.55-2.85(br, 3H), 3.78(brs, 2H),                                             4.06(brs, 2H), 5.77(d, J=8.1Hz, 1H),                                          8.78(s, 1H), 9.24(s,                                                                             Et.sub.3 N                                                                    CH.sub.3 CN            243 Me                                                                                ##STR236##                                                                                  ##STR237##                                                                     Pale yellow solid                                                                    221-224.5                                                                           [DMSO-d.sub.6 ] δ; 2.11(s, 6H),                                         .4-2.6(m, 2H), 2.71(s,                                                        3H), 2.75-2.9(br, 1H), 3.7(brs, 2H),                                          4.12(brs, 2H), 5.81(d, J=8.1Hz, 1H),                                          8.8(s, 1H), 9.23(s,                                                                              Et.sub.3 N                                                                    CH.sub.3 CN            __________________________________________________________________________

                                      TABLE 49                                    __________________________________________________________________________    Compound:                                                                      ##STR238##                                                                   Compound                    Melting point                                     No.   R.sup.2                                                                         Y          Z Property                                                                             (°C.)                                                                         .sup.1 H-NMR       Solvent                 __________________________________________________________________________    244   H                                                                                ##STR239##                                                                              N Pale yellow solid                                                                    279-280.5                                                                            [DMSO-d.sub.6 ] δ; 1.45-1.7(m,                                          2H), 2.0-2.15(m, 2H), 2.31(s, 3H),                                            3.05-3.25(m, 2H), 4.1-4.25(m, 2H),                                            8.17(d, J=13.7Hz, 1H), 8.36(brs, 3H)                                          8.96(s, 1H)                                                                                       ##STR240##             245   H                                                                                ##STR241##                                                                              N Colorless solid                                                                      244-245                                                                              [DMSO-d.sub.6 ] δ; 2.32(s, 3H),                                         3.8-4.7(m, 3H), 8.04(d, J=11.1Hz, 1H),                                        .86(s, 1H)         Et.sub.3 N CH.sub.3                                                           CN                      __________________________________________________________________________

EXAMPLE 156 7-{3-(S)-(2-(S)-t-Buthoxycarbonylaminopropionyl)aminopyrrolidin-1-yl}-6-fluoro-1-(4-methyl-1,2,5-oxadiazol-3-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (Compound No.246)

A solution of Boc-L-alanine (190 mg), 1-hydroxybenzotriazole (153 mg),WSC hydrochloride (192 mg) and triethylamine (101 mg) in chloroform (10mg) was stirred at room temperature for 0.5 hour. To this solution wasadded a solution of compound No.81 (370 mg) in DMF (10 ml), then stirredat 50° C. for 1 day. After evaporation of the solvent, an aqueous 5%citric acid solution (20 ml) was added, then extracted with chloroform(100 ml). The organic phase was dried (MgSO₄) and removed. Afteraddition of isopropylether for solidification, the precipitate wasfiltrated. The title compound No. 246 was obtained as a yellow solid.

Melting point: 205.5°-207.5° C. ¹ H-NMR(CDCl₃) δ; 1.33(d,J=6.8 Hz,3H),1.40(s,9H), 2.2(brs,2H), 2.35(s,3H), 4.1(brs,1H), 4.55(brs,1H),5.03(brs,1H), 7.0-7.2(br,1H), 8.0(d,J=12 Hz,1H), 8.57(s,1H)

EXAMPLE 1577-{3-(S)-(2-(S)-Aminopropionyl)aminopyrrolidin-1-yl}-6-fluoro-1-(4-methyl-1,2,5-oxadiazol-3-yl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride(Compound No. 247 ) Method a

Compound No.246 (90 mg) was dissolved in chloroform (10 ml) and4N-HCl/dioxane (1 ml). The solution was stirred at room temperature for20 minutes. After evaporation of the solvent, ether was added. Theprecipitate was filtrated. The title compound No. 247 was obtained as ayellow solid (80 mg).

Method b

Compound No.78 (2.1 g) synthesized in Example 39 and3-(S)-aminopyrrolidine (0.86 g) was dissolved in chloroform (50 ml). Thesolution was stirred at room temperature for 10 hours. After evaporationof the solvent, ether was added to obtain a red solid (2.4 g).

To a solution of Boc-L-alanine (945 mg) and N-methylmorpholine (505 mg)in dichloromethane (20 ml), 0.65 ml of isobutylchloroformate was addedwith ice cooling. Then the solution was stirred for 20 minutes. To thissolution was added the red solid (2.01 g) obtained above, then stirredat room temperature for 30 minutes. The reaction solution was washedwith aqueous 5% citric acid, aqueous 5% NaHCO₃ and water successively.The organic phase was dried (MgSO₄) and evaporated. To the residue wasadded ether (20 ml). The precipitate was filtrated to obtain a pale redsolid (2.5 g).

This compound is an ethyl ester derivative of compound No.244.

Melting point: 107°-113° C. ¹ H-NMR(CDCl₃) δ; 1.2-1.5(m,15H),1.95-2.2(br,2H), 2.22(s,3H), 3.7-4.0(br,1H), 4.2-4.3(m,3H),4.55-4.8(br,1H), 7.64(d,J=12 Hz,1H), 8.41(s,1H)

This red solid (1.5 g) was dissolved in tetrahydrofuran (30 ml) and6N-HCl (5 ml). The solution was stirred at room temperature for 48hours. After evaporation of the solvent, ethanol was added to theresidue. The precipitate was filtrated. The title compound No. 247 wasobtained as a yellow solid (0.98 g).

Melting point: 223.0°-225.0° C. ¹ H-NMR(DMSO-d₆) δ; 1.32(d,J=6.8 Hz,3H),1.8-2.2(m,2H), 2.33(s,3H), 3.2-4.2(m,4H), 4.35(brs,1H), 8.08(d,J=12.4Hz,1H), 8.26(brs,3H), 8.90(s,1H), 9.0(d,lH)

EXAMPLE 158

Compound Nos. 248-252 listed in Tables 50 and 51 were synthesized in asimilar manner to Example 11, proceeding from the compound No.3.

                                      TABLE 50                                    __________________________________________________________________________    Compound:                                                                      ##STR242##                                                                   Compound                     Melting point                                    No.   R.sup.2                                                                         Y           Z Property                                                                             (°C.)                                                                         .sup.1 H-NMR       Solvent                __________________________________________________________________________    248   H                                                                                ##STR243## N Pale yellow solid                                                                    258.5-259.5                                                                          [DMSO-d.sub.6 ] δ; 1.5-1.85(m,                                          3H), 1.99(brs, 1H), 3.2-3.55(m, 3H),                                          3.7-3.85(m, 1H), 4.05-4.2(m, 1H),                                             8.21(d, J=12.8Hz, 1H), 8.38(brs, 3H),                                         .01(s, 1H), 9.33(s,                                                                               ##STR244##            249   H                                                                                ##STR245## N Colorless solid                                                                      Decomposed from 272                                                                  [DMSO-d.sub.6 ] δ; 2.77(s, 6H),                                         .2-4.8(m, 5H), 8.19(d, J=11.5Hz, 1H),                                         .03(s, 1H), 9.33(s,                                                                              "H)                    250   H                                                                                ##STR246## N Pale yellow solid                                                                    247-250                                                                              [DMSO-d.sub.6 ] δ; 1.45-1.68(m,                                         2H), 1.9-2.1(m, 2H), 3.07-3.25(m,                                             2H), 4.1-4.3(m, 2H), 8.2(d, J=13Hz,                                           1H), 8.18(brs, 3H), 9.02(s, 1H),                                              9.28(s, 1H)        "                      __________________________________________________________________________

                                      TABLE 51                                    __________________________________________________________________________    Compound                    Melting point                                     No.   R.sup.2                                                                         Y           Z  Property                                                                           (°C.)                                                                           .sup.1 H-NMR     Solvent                 __________________________________________________________________________    251   H                                                                                ##STR247## N  Colorless powder                                                                   214-216 (Decomposed)                                                                   [DMSO-d.sub.6 ] δ;                                                      1.60-1.85(m, 5H), 3.15-3.22(m, 1H),                                           3.51-4.15(m, 6H), 8.17(d, J=12.8Hz,                                           1H), 9.02(s, 1H), 9.30(brs,                                                                     ##STR248##             252   H                                                                                ##STR249## N  Colorless powder                                                                   215-218 (Decomposed)                                                                   [DMSO-d.sub.6 ] δ;                                                      1.60-1.85(m, 5H), 3.15-3.22(m, 1H),                                           3.51-4.15(m, 6H), 8.17(d, J=12.8Hz,                                           1H), 9.02(s, 1H), 9.30(brs,                                                                    "H)                     __________________________________________________________________________

Now, synthetic methods of 3-amino-4-methyl-1,2,5-thiadiazol aredescribed as reference examples:

Reference Example 1 4-Methyl-1,2,5-thiadiazol-3-carboxylic acid(Compound A)

To a mixture of sulfur monochloride (220 ml) and DMF (400 ml) was added75 g of 2,3-diaminobutylic acid dihydrobromide with ice cooling, thenstirred at room temperature for 2 hours. This solution was poured intowater (3 liters), then extracted with ether (3L×4). The ether wasremoved in vacuo. The residue was dissolved in 5% aqueous NaHCO₃solution (200 ml) and washed with 100 ml of carbondisulfide. After thesolution was acidified with c-HCl it was extracted with ether (1.3L×2).The organic phase was dried (MgSO₄) and concentrated in vacuo. The titlecompound (A) was obtained as a pale yellow solid (7.5 g).

Melting point: 123°-129° C. ¹ H-NMR(DMSO-d₆) δ; 2.72(s,3H)

Reference Example 2 3-t-Buthoxycarbonylamino-4-methyl-1,2,5-thiadiazole(Compound B)

A solution of compound A (7.5 g), triethylamine (5.8 g) anddiphenylphosphorylazide (15.7 g) in 2-methyl-2-propanol (200 ml) wasstirred for 20 hours under reflux with heating. The solvent was removed.After addition of ethyl acetate (500 ml), the solution was washed withwater, 5% aqueous citric acid, and 5% aqueous NaHCO₃ successively,followed by drying (MgSO₄) and distilation. The residue was purified bycolumn chromatography on silicagel(chloroform as an eluent). The titlecompound (B) was obtained as a colorless solid (10.4 g).

Melting point: 124°-128° C. ¹ H-NMR(CDCl₃) δ; 1.53(s,9H), 2.50(s,3H),7.1(brs,1H)

Reference Example 3 3-Amino-4-methyl-1,2,5-thiadiazole, hydrochloride(Compound C)

Compound B (15.2 g) was dissolved in ethanol (200 ml) and c-HCl (35 ml).The solution was stirred at 50° C. for 4 hours. After evaporation of thesolvent, 100 ml of chloroform was added. The precipitate was filtrated.The title compound was obtained as a yellow solid (7.7 g).

Melting point: 121°-124° C. ¹ H-NMR(DMSO-d₆) δ; 2.31(s,3H), 7.55(brs,3H)

EXAMPLE 159

Antibacterial activity, absorption and excretion of the compoundsindicated in Examples were tested as follows.

(1) Antibacterial activity

The minimum inhibitory concentration (MIC: microgram/ml) is measured bythe standard method of Japan Society of Chemotherapy, (Chemotherapy,Volume 29, No.1, pp.76-79, 1981). The results are shown in Table 52 inwhich compound numbers are the same as those indicated in Examples.

                  TABLE 52                                                        ______________________________________                                                Minimum Inhibitory Concentration (micro-g/ml)                         Compound                                                                              E. Coli NIH JC-2                                                                            S. aureus 209P                                                                            P. aeruginosa                               No.     (IFO* 12734)  (IFO 12732) (IFO 3445)                                  ______________________________________                                        18      <0.013        0.2         0.1                                         19      <0.013        0.1         0.39                                        58      0.05           1.56       0.39                                        81      0.05          0.1         0.2                                         126     3.13           0.39       3.13                                        162      0.013        0.1         0.2                                         187     0.05          0.2         0.39                                        ______________________________________                                         *Institute of Fermentation, Osaka                                        

(2) Absorption and excretion

The absorption and excretion after oral administration of the compoundsof the present invention were tested by measuring the recovery in urineand bile as follows.

(a) Recovery in urine

To a group of three male JCL-SD rats (6 weeks old) fasted overnight, asubject compound was orally administered as prepared to be 20 mg/10ml/kg with 0.5% of methylcellulose solution. The sampling was carriedout by collecting urine in 0 to 6 hours and 6 to 24 hours. Theconcentration of the subject compound in the urine was examined by adisk method by using Bacillus subtilis ATCC 6633 as a testing bacillusto obtain an excretion rate in urine for 24 hours.

(b) Recovery in bile

A subject compound was prepared in the same manner as the recovery testin urine and was orally administered to the rats. The bile was collectedby using a polyethylene tube inserted into the choledochus over 24hours. The concentration of the subject compound in the bile sample wasexamined in the same manner as the recovery in urine to obtain anexcretion rate in bile for 24 hours.

The results are shown in Table 53.

                  TABLE 53                                                        ______________________________________                                                       Excretion Rate (24 hours, %)                                   Compound No.     In Urine In Bile                                             ______________________________________                                        18               20       2                                                   19                 80.6   4.4                                                 ______________________________________                                    

As described above, according to the present invention, the compoundsrepresented by formula(1) and salts thereof, which are novel compounds,exhibit an extremely excellent antibacterial activity againstgram-negative and gram-positive bacteria and possess a high oralabsorbability.

Industrial Applicability

According to the present invention, the compounds represented by formula(1) and salts thereof are extremely valuable as antibacterial agents andvery safe. Accordingly, they can be used as not only pharmaceuticals ormedicines for the human body and animals but also medicines for fishes,agricultural chemicals and preservatives for foods. Further, thecompounds of this invention are expected to have an anti viral action,especially an anti-HIV (human immuno deficiency virus) action, andtherefore is considered to have preventive or curative activitiesagainst the AIDS.

We claim:
 1. A quinolone derivative represented by the formula (1), or asalt thereof: ##STR250## wherein R¹ represents a hydrogen atom, or acarboxyl protective group, R² represents a hydrogen atom, halogen atomor a lower alkyl group, X represents a hydrogen atom or a halogen atom,Y represents a halogen atom, a cyclic amino group having one or morenitrogen atoms as part of the ring and which group may have asubstituent, a cyclo-lower alkenyl group which may have a substituent,or a group R³ -(CH₂)_(m) --A-- (wherein R.sup.³ represents a hydrogenatom or an amino group which may have a substituent, A represents anoxygen atom or a sulfur atom and m represents a number of 0 to 3), Zrepresents a nitrogen atom or a group C--R⁴ (wherein R⁴ represents ahydrogen atom or a halogen atom), W represents a five-memberedheterocyclic group which may have a substituent and which has 3 or morehetero-atoms, among which at least 2 hetero-atoms are nitrogen atoms,and n represents a number of 0 to
 2. 2. A quinolone derivative or a saltthereof according to claim 1, wherein said cyclic amino grouprepresented by Y which may have a substituent is selected from the groupconsisting of saturated or unsaturated monocyclic 3 to 7 membered cyclicamino groups having one nitrogen atom, saturated or unsaturatedmonocyclic 3 to 7 membered cyclic amino groups having two nitrogenatoms, saturated or unsaturated monocyclic 3 to 7 membered cyclic aminogroups having three or more nitrogen atoms, and saturated or unsaturatedmonocyclic 3 to 7 membered cyclic amino group further having ahetero-atom selected from the group consisting of oxygen and sulfur. 3.A quinolone derivative or a salt thereof according to claim 1, whereinsaid group represented by W is selected from the group consisting ofthiadiazolyl group, triazolyl group, oxadiazolyl group and tetrazolylgroup, each of which may have a substituent.
 4. An antibacterial agentcomprising the quinolone derivative or a salt thereof according to claim1.